JP2012246252A - Modified-release type particle pharmaceutical composition for oral administration, method for producing the same, and orally disintegrating tablet including the composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a modified-release type particle pharmaceutical composition (MRP) designed not to substantially release a drug component while remaining in an oral cavity after administration, and to start releasing the drug component immediately after entering a stomach, an orally disintegrating particle composition (ODP) containing the MRP composition, and method for producing them.SOLUTION: The modified-release particle pharmaceutical composition (MRP), which is the multilayer particle pharmaceutical composition for oral administration, includes at least: a nuclear particle containing pharmaceutically acceptable organic acid; an active ingredient-containing layer arranged on the outside of the organic acid-containing nuclear particle and including a slightly acidic or basic active ingredient; and a gastrosoluble coating layer outside the active ingredient-containing layer. Between the organic acid-containing nuclear particle and the active ingredient-containing layer, a slow-release coating layer may be arranged further. The orally disintegrating particle composition (ODP) and an orally disintegrating tablet (ODT) including the MRP and inactive rapidly disintegrating particles are also provided.

Description

  The present invention relates to a controlled release particulate pharmaceutical composition for oral administration (“Modified-release particles”: “MRP”), and a collapsible particulate composition for oral administration containing the composition (“ “Orally disintegrating particles” or “Orodispersible particles”: In this specification, “ODP” may be abbreviated as “ODP”) and orally disintegrating tablets (also referred to herein as “orally disintegrating tablets”, or “Orally disintegrating tablet "or" Orodispersible tablet ": abbreviated as" ODT "), and a method for producing them. More specifically, after taking, the drug component is not substantially released while the composition remains in the oral cavity, and is precisely controlled to start releasing immediately after moving into the stomach. The present invention relates to a particulate pharmaceutical composition (MRP), an orally disintegrating particulate composition (ODP) and an orally disintegrating tablet (ODT) containing the composition, and methods for producing them.

  A synthetic imidazotriazinone derivative vardenafil is known as a cGMP phosphodiesterase (PDE) 5 inhibitor and its activity spectrum (for example, JP-T-2001-522851 (Patent Document 1)). Vardenafil can be purchased under the name Levitra® and is exclusively used as an immediate release (IR) tablet for the treatment of erectile dysfunction. This immediate release vardenafil pharmaceutical dosage form has satisfied a targeted profile for treatment that can be adapted to patient needs through their rapid onset of action and relatively short duration of action. The preferred absorption profile of vardenafil is the upper gastrointestinal system (Upper Gastrointestinal Tract: "U-GIT"), which is part of the stomach and duodenum in the gastrointestinal system (Gastrointestinal Tract: "GIT"). It may be abbreviated as “upper GI tube”)). Since vardenafil is a basic drug, the stomach in a strongly acidic state is considered to be the main dissolution site of vardenafil.

On the other hand, immediate release tablets containing vardenafil need to be applied orally with water to facilitate rapid swallowing and efficient release of active ingredients. Considering the situation where patients take vardenafil, it seems that the convenience of patients will be greatly enhanced if they can be taken without water.
In recent years, dosage forms that have improved the convenience of patients when taking drugs have attracted attention, and in particular, orally disintegrating tablets and orally disintegrating films that can be taken without water and are easy to swallow have been developed one after another. Has been. However, there are many active ingredients that are not suitable for application of such orally disintegrating preparations. Typically, when the active ingredient has an unpleasant taste such as a bitter taste, the active ingredient released in the oral cavity gives a strong discomfort to the patient and significantly lowers compliance. In addition, when the active ingredient is absorbed into the oral cavity, there are concerns that side effects that have not been observed in normal preparations taken with water will develop and cause problems such as an increase in individual differences in drug efficacy. Furthermore, when the active ingredient has an undesired direct action on the oral cavity or esophagus, it is considered that adaptation is more difficult. This applies to vardenafil, which is known for its strong bitterness and absorption in the oral cavity.

  In order to improve convenience while avoiding the above problems, it is necessary to suppress the release of active ingredients in the oral cavity for a certain period of time in an oral particulate pharmaceutical composition. On the other hand, in order for the active ingredient to exhibit a sufficient medicinal effect, it is necessary to release the active ingredient from the oral particulate pharmaceutical composition and absorb it in a sufficient amount. For this purpose, after the release of the active ingredient from the oral particulate pharmaceutical composition for a certain period of time, the active ingredient is rapidly released before the oral particulate pharmaceutical composition moves to the lower part of the digestive tract. Desirably absorbed at the top. Moreover, it is desirable that the time for suppressing the active ingredient release (lag time) and the subsequent dissolution rate can be appropriately controlled according to the characteristics of the active ingredient.

  However, it is impossible to achieve both the complete suppression of the initial dissolution and the subsequent rapid dissolution from the prior art. For example, when a sustained-release film is used to suppress initial dissolution, it is difficult to quickly release the active ingredient thereafter. In addition, when the initial dissolution in the oral cavity is completely suppressed with a gastric film, the active ingredient is not absorbed at all in patients with gastric hypoacidity or gastric anacidosis. Even in the combination of a sustained-release film and a gastric-soluble film, or a combination of a sustained-release film and a water-soluble film, suppression of initial active ingredient elution, rapid release of the active ingredient thereafter, and control of lag time, It is extremely difficult to satisfy these simultaneously.

  Conventionally, after suppressing the elution of the active ingredient in the initial stage, a mixture containing a water-insoluble substance and a water-soluble substance is applied to the preparation containing the water-soluble active ingredient to quickly release the active ingredient. The method is generally used (for example, Japanese translations of PCT publication No. 2004-532257 (patent document 2)). Until the water-soluble substance in the mixed film is dissolved, the infiltration rate of water into the preparation is suppressed, and the initial elution of active ingredients can be suppressed. Thereafter, when the water-soluble substance in the film is dissolved, pores are formed in the film and the water infiltration speed is accelerated, so that the active ingredient can be released quickly. However, in this method as well, if the film is thin, the lag time is insufficient, and if the film is thick, rapid release of active ingredients is suppressed, making it difficult to achieve both.

  On the other hand, Japanese Patent No. 4277904 (Patent Document 3) discloses (i) a core particle containing a drug having an unpleasant taste at the center of a particulate pharmaceutical composition, and (ii) two kinds of water-soluble components in an intermediate layer. Orally used for orally disintegrating tablets, comprising a layer containing an insolubilization accelerator and an insolubilizing substance, and (iii) a water infiltration amount control layer for controlling the water infiltration rate in the outermost layer. Disclosed is a time-release particulate pharmaceutical composition for administration. As an example of the layer (ii) containing an insolubilization accelerator and an insolubilizing substance, an acid-type insolubilization accelerator (citric acid, malic acid, tartaric acid, etc.) and an acid insolubilizing substance (L, LD, S of methacrylic acid copolymer) And the like, and specific examples of the water penetration amount control layer of (iii) include ethyl cellulose and aminoalkyl methacrylate copolymer RS, LD, E, L, LD, and S. However, this disclosed composition uses a manufacturing process using an organic solvent harmful to the environment, has difficulty in sustained-release film strength, and increases the thickness of the sustained-release film; In the case of small particles with less foreign body feeling, rapid drug release after sufficient lag time is not successful, and release after lag time is somewhat sustained, so there is still a problem with individual specific drugs. Is leaving. That is, for example with respect to vardenafil, it is difficult to apply the disclosed composition to achieve a target profile of vardenafil for treatment that can quickly meet the needs of the patient after a predetermined controlled lag time.

  Japanese Patent No. 3350059 presents a three-layer oral dosage form that releases rapidly in the gastrointestinal tract and masks the taste. Specifically, the drug is selected from the anti-impotence drug sildenafil, (i) core particles composed of the drug and microcrystalline cellulose, and (ii) the water-soluble polymer hydroxypropylmethylcellulose and the water-insoluble polymer methacrylic. Disclosed is a three-layer particle dosage form comprising an inner coating layer comprising an acid salt copolymer NE, and (iii) an aminoalkyl methacrylate copolymer E insoluble in saliva, and an outer coating layer comprising talc, if necessary. ing. However, according to the inventors' knowledge, the initial elution lag time and subsequent rapid release characteristics are still insufficient.

  JP 2009-524698 (Patent Document 5) discloses one or more of weakly basic drugs, immediate release (IR) beads, sustained release (SR) beads and / or timed pulsed release (TPR) beads. A pharmaceutical multiparticulate dosage form comprising means, comprising an organic acid (citric acid, fumaric acid, malic acid, etc.) as a solubilizing agent separated from the drug, and the organic acid is not depleted until the drug is completely released A multiparticulate dosage form is disclosed. The IR beads used here are taste-masked IR beads, and, as a specific embodiment of the layer structure, (i) an acid core in which sugar spheres are laminated with fumaric acid, and (ii) the acid core An SR layer coated with insoluble ethylcellulose and triethylcitric acid; (iii) a drug layer coated with the antihypertensive agent carvedilol; and (iv) the drug layer coated with enteric ethylcellulose / gastric methacrylic acid. An IR bead having a four-layer structure comprising an outer layer coated with a 50/50 mixture of aminoalkyl copolymer E is disclosed. However, according to the knowledge of the present inventors, for example, when the anti-sympathetic drug vardenafil is used as a drug, the desired elution lag time can be obtained, but the subsequent rapid release characteristics are insufficient.

  JP-T-2008-531614 (Patent Document 6) discloses a novel orally disintegrating preparation of vardenafil that dissolves rapidly in the mouth, leading to an increase in bioavailability and a plateau-type plasma concentration curve.

  However, the bioavailability of vardenafil obtained there deviates from the target profile found in immediate release (IR) tablets currently applied exclusively as Levitra® and the initial lag time is obtained. Absent.

  As mentioned above, the anti-sympathetic drug vardenafil, a PDE5 inhibitor, is currently only known as an immediate release tablet for acute treatment of erectile dysfunction, while it has been used to date However, pharmaceutical forms of the PDE5 inhibitor vardenafil, which are exclusively for immediate release, have met their targeted profiles for treatments that can respond quickly to certain requirements through their rapid onset of action and relatively short duration of action. .

  Therefore, the particulate pharmaceutical composition and / or the orally disintegrating tablet comprising the particulate pharmaceutical composition with improved convenience when the patient takes the medicine can be taken without water and can be swallowed. Since it is easy, development of a controlled-release dosage form for oral administration is awaited as a dosage form of vardenafil. To that end, how to match the dissolution profile of vardenafil with that of a commercial product in the dosage form is a big problem.

JP-T-2001-522851 JP-T-2004-532257 Japanese Patent No. 4277904 Patent No. 3350059 Special table 2009-524698 Special table 2008-531614 gazette

  The object of the present invention is to solve the above-mentioned problems, i.e. avoiding and reducing the taste of the drug, oral absorption, direct action on the oral cavity or esophagus, etc. To provide a formulation, for this purpose, to release the drug at any rate after any lag time. That is, in a granular preparation designed to orally administer a weakly acidic or basic active ingredient without water, it has a sufficiently long lag time and immediately starts to release the drug after the lag time. And a controlled release particulate pharmaceutical composition (MRP) capable of arbitrarily controlling the length of lag time and the subsequent dissolution rate according to the characteristics and purpose of the active ingredient and the preparation, and oral administration containing the composition It is to provide a disintegrating particulate composition (ODP) and an orally disintegrating tablet (ODT). Furthermore, a controlled release particulate pharmaceutical composition capable of releasing an active ingredient at the same rate as a normal tablet after a predetermined lag time even when taken without water regardless of the acidity in the stomach of the patient. (MRP) and the like.

  As a weakly acidic or basic active ingredient, for example, the problem of the present invention is specifically described with vardenafil, which is a basic drug, and is a commercially available product (Levitra (registered trademark) which is an immediate release tablet (IR tablet)). Controlled release particulate pharmaceutical composition (MRP) of vardenafil, which can be administered orally without water, showing an elution profile that matches the elution profile of: and an orally disintegrating particulate composition (ODP) containing the composition ) And orally disintegrating tablets (ODT). In the case of vardenafil, if there is no sustained release film, the release is too early and adjustment is necessary.

In order to solve the above-mentioned problems, the present inventors have come up with an idea that a technique of covering with a plurality of layers having clearly different roles is effective, and as a result of diligent research, they have surprisingly solved the above-mentioned problems. The present invention has been reached.
That is, the present invention relates to a multi-layered particulate pharmaceutical composition for oral administration, comprising at least a core particle containing a pharmaceutically acceptable organic acid, a weakly acidic or basic base outside the organic acid-containing core particle. A controlled release particulate pharmaceutical composition (Modified) comprising an active ingredient-containing layer containing an active ingredient having a sexual activity (sometimes abbreviated as “drug-containing layer”) and a gastric soluble coating layer outside the drug-containing layer -release particles: "MRP" may be abbreviated.)
Furthermore, the present invention is characterized in that the pharmaceutical composition is configured such that drug release from the pharmaceutical composition does not substantially occur in the oral cavity and then rapidly occurs in the upper gastrointestinal tract. Provided are a controlled release particulate pharmaceutical composition (MRP) and a method for its production.
The present invention also provides a disintegrating particulate composition for oral administration (ODP) and an orally disintegrating tablet (ODT) containing the controlled release particulate pharmaceutical composition, and a method for producing them.

In the multilayer controlled-release particulate pharmaceutical composition (MRP) of the present invention, even when administered orally without water, a sufficiently long lag time is obtained, and drug release is promptly performed after the lag time. Can be started. Furthermore, the length of the lag time and the subsequent release rate can be arbitrarily controlled according to the characteristics and purpose of the drug and the preparation. Moreover, the same effect can be acquired also when it applies to a stomach anacidosis patient without water.
The MRP of the present invention has a core particle containing a pharmaceutically acceptable organic acid, a drug-containing layer containing a drug on its outer side, and an outer liquid (saliva etc.) penetration rate inside the preparation on its outer side. A particulate pharmaceutical composition coated with a gastric soluble coating layer as an external fluid (saliva, etc.) infiltration control layer to be controlled, having a sufficiently long lag time in the oral cavity, and upper digestion after the lag time The drug can be rapidly released by a tube (U-GIT), and the length of lag time is changed within a range of about 3 to 15 minutes, preferably 5 to 10 by changing the coating amount and the components of each coating layer. It has a feature that it can be controlled within a range of minutes (for example, 10 minutes). There is no substantial release of a weakly acidic or basic active ingredient (eg, vardenafil, a basic drug) during the lag time, and a weakly acidic or basic drug (eg, vardenafil) is released immediately after the lag time is over It is preferable.
Here, the definition of the lag time in the present invention (sometimes referred to as lag time in the present specification) will be described below.
For the definition of lag time, see “Regarding Generic Drugs” in Drug Medication Review Issue No. 1124004, which was sent to the Director of the Prefectural Sanitation Supervising Department (Department) on November 24, 2006 by the Director of the Examination Management Division, Ministry of Health, Labor and Welfare. “Partial revision of guidelines for bioequivalence testing, etc.” “Appendix 1, page 19” states that “the time required for the drug to elute from the preparation to 5% of the indicated content is the lag time”. Further, in general masking of bitterness, for example, if no bitterness is felt even if 20% is eluted, it may be defined as the time required until 20% is eluted. However, the present invention assumes a scene in which a stricter lag time standard is substantially obtained with substantially no initial leakage, for example, a scene where the contribution of oral absorption cannot be ignored. Therefore, in the present invention, the lag time is defined as “time required for 1% elution”. The calculation method of the lag time of the present invention is as follows: “Ministry of Health, Labor and Welfare, Pharmaceutical and Food Affairs Bureau, Administration and Administration Division,” November 24, 2006. This is in accordance with “Procedure 1) Calculation of lag time” described in Attachment 1 pp. 24-25 “Amendments to“ Q & A ”on Bioequivalence Guidelines for Pharmaceuticals”.
Calculation formula of time tA for elution rate to reach dA% for each elution curve tA = t1 + (dA−d1) X (t2−t1) / (d2−d1)
here,
t1: Measurement time immediately before the elution rate reaches dA% t2: Measurement time immediately after the elution rate exceeds dA% d1: Elution rate at time t1 d2: Elution rate at time t2 where dA = 1%

  The organic acid in the organic acid-containing core particles in the present invention is a pharmaceutically acceptable organic acid. The organic acid has a function of controlling the release of a weakly acidic or basic active ingredient by dissolving the gastric film layer. That is, the start of elution of the organic acid is completely synchronized with the start of elution of the weakly acidic or basic active ingredient, but the subsequent elution profiles do not necessarily match. The organic acid moves from the core particle to the outer layer within a period corresponding to a predetermined lag time by the external liquid (saliva etc.) entering through the gastric film layer, and a part or part of the gastric film layer is transferred. All are dissolved and the elution of the organic acid itself is complete. The drug elutes at a rate depending on the surface area exposed by dissolution of the gastric film.

According to the present invention, in a preparation designed for oral administration of a weakly acidic or basic active ingredient, the drug has a sufficiently long lag time, can be released quickly after the lag time, and Depending on the characteristics and purpose, the controlled release particulate pharmaceutical composition (MRP) for oral administration capable of arbitrarily controlling the length of lag time, and the collapsible particulate composition for oral administration containing the composition ( ODP) and orally disintegrating tablets (ODT) can be obtained.
Specifically, vardenafil can be taken without water as MRP, ODP or ODT and is easy to swallow. Furthermore, since the elution profile of vardenafil can be matched with the elution profile of a commercial product, it can be applied without impairing the established blood concentration of vardenafil, and further, the effectiveness and safety.

FIG. 1 shows a cross-sectional view of a multilayer structure of MRP (without SR layer) (Example 1). The display of the sealing layer between layers is omitted. FIG. 2 shows a cross-sectional view of a multilayer structure of MRP (with SR layer) (Example 2). The display of the sealing layer between layers is omitted. FIG. 3 shows a cross-sectional view of a multilayer structure of the particulate pharmaceutical composition (without an organic acid-containing layer) used in Comparative Example 1. The display of the sealing layer between layers is omitted. FIG. 4 shows the dissolution profile of vardenafil in each MRP and Control (commercial product Levitra (registered trademark) 10 mg) of Comparative Formulation Examples 1 to 4 at pH 1.2 (50 rpm) (Example 3). FIG. 5 shows the dissolution profile of vardenafil in each MRP and Control (commercial product Levitra (registered trademark) 10 mg) of Comparative Formulation Examples 1 to 4 at pH 6.8 (50 rpm) (Example 3). FIG. 6 shows the dissolution profile of vardenafil in each MRP and Control (commercial product Levitra (registered trademark) 10 mg) of Preparation Examples 1 to 4 at pH 1.2 (50 rpm) (Example 3). FIG. 7 shows the dissolution profile of vardenafil in each MRP and Control (commercial product Levitra (registered trademark) 10 mg) of Preparation Examples 1 to 4 at pH 6.8 (50 rpm) (Example 3). FIG. 8 shows the dissolution profile of vardenafil in each MRP and Control (commercial product Levitra (registered trademark) 10 mg) of Preparation Examples 5 to 10 at pH 1.2 (50 rpm) (Example 3). FIG. 9 shows the dissolution profile of vardenafil in each MRP and Control (commercial product Levitra (registered trademark) tablets 10 mg) of Preparation Examples 5 to 10 at pH 6.8 (50 rpm) (Example 3). FIG. 10 shows the dissolution profile of vardenafil in each MRP and Control (commercial product Levitra® tablets 10 mg) of Preparation Examples 11 to 18 at pH 6.8 (100 rpm) (Example 3). FIG. 11 shows contrast of elution profiles of vardenafil and fumaric acid in the MRP of Formulation Example 12 at pH 1.2 (50 rpm), pH 5.0 (50 rpm), and pH 6.8 (50 rpm) (Example 4). FIG. 12 shows dissolution profiles of vardenafil in MRP of Formulation Example 12, ODP of Formulation Example 19, and Control (commercially available Levitra® tablets 10 mg) at pH 1.2 (50 rpm) (Examples 4 and 6). ). FIG. 13 shows dissolution profiles of vardenafil in MRP of Formulation Example 12, ODP of Formulation Example 19 and Control (commercial product Levitra® Tablets 10 mg) at pH 6.8 (50 rpm) (Examples 4 and 6). ). FIG. 14 shows the dissolution profiles of vardenafil in MRP of Formulation Example 20 and ODT of Formulation Example 21 at pH 1.2 (50 rpm) (Examples 3 and 6). FIG. 15 shows the dissolution profiles of vardenafil in MRP of Formulation Example 20 and ODT of Formulation Example 21 at pH 6.8 (50 rpm) (Examples 3 and 6). FIG. 16 shows the dissolution profile of vardenafil in ODP and Control (commercial product Levitra® tablets 20 mg) of formulation examples 22-24 at pH 6.8 (100 rpm) (Example 6).

Hereinafter, embodiments of the present invention will be described in detail.
First, the layer structure of the controlled release particulate pharmaceutical composition (MRP) of the present invention will be described. The controlled release particulate pharmaceutical composition (MRP) used for oral administration of the present invention has, as its basic layer structure, an organic acid-containing core particle (core) at the center of the particle, and a weakly acidic or base on the outside. It is a particle having a basic layer constitution of a multilayer structure comprising a drug-containing layer (drug layer) containing an active drug component (API) as an active ingredient and a gastric film layer on the outer side thereof in this order.
The controlled release particulate pharmaceutical composition (MRP) may have a sustained release coating layer (SR layer) between the organic acid-containing core particles and the drug-containing layer. The sustained-release coating layer (SR layer) is not particularly limited as long as it has properties as a semipermeable membrane, but preferably contains ethyl cellulose or ethyl acrylate / methyl methacrylate copolymer.
The organic acid-containing core particles may be particles in which the organic acid itself is made into a spherical shape, or the organic acid-containing layer is coated on the outer side of the inert core. As the inert core, crystalline cellulose grains (synonymous with crystalline cellulose (grains), also referred to as crystalline cellulose (grains) or cellulose spheres in this specification), sucrose / starch spherical granules, purified white sugar spheres At least one selected from the group consisting of granules, lactose / crystalline cellulose spherical granules and mannitol spherical granules is preferred, and crystalline cellulose (grains) is particularly preferred.
At least one surface of the organic acid-containing core particles, sustained-release coating layer, drug-containing layer, and gastric soluble coating layer may be coated with a seal coat coating layer. It is preferable to coat each of the organic acid-containing core particles, the sustained-release coating layer and the drug-containing layer with a seal coat coating layer. The seal coat film layer is not particularly limited as long as it is a water-soluble coating layer, and examples thereof include a seal coat coating layer containing hypromellose (hydroxypropylmethylcellulose), methylcellulose, etc., and macrogol ( A plasticizer such as polyethylene glycol) can be added. Another example of the seal coat layer is surface modification with a sugar alcohol such as erythritol, which is usually used by mixing with a binder such as popidone or hydroxypropylcellulose. In these, the seal-coat coating layer containing a hypromellose or methylcellulose is preferable.

  The controlled release particulate pharmaceutical composition (MRP) of the present invention is configured such that drug release from the pharmaceutical composition does not substantially occur in the oral cavity and then rapidly occurs in the upper gastrointestinal tract. It is characterized by that. The gastric film of the present invention does not dissolve in the oral cavity where the pH is near weak acidity, and therefore substantially prevents the active drug component from eluting in the oral cavity (this period is referred to as lag time), for example, Eliminate patient discomfort due to unpleasant taste of active ingredients. The lag time may be in the range of 3-15 minutes, preferably 5-10 minutes (eg 10 minutes). After a lag time caused by the time that external liquid (saliva, etc.) enters through the gastric film from the outside of the particle, the organic acid is eluted from the organic acid-containing core particles, and this organic acid removes part or all of the gastric film. Dissolve at desired rate.

  As described above, the controlled release particulate pharmaceutical composition (MRP) of the present invention is characterized in that the release of a weakly acidic or basic active ingredient starts when the organic acid dissolves the gastric film layer from the inside. To do. This feature will be described below. That is, the main function of the organic acid in the present invention is to dissolve the gastric film of the outer layer, and is a mechanism that does not reduce bioavailability even in hypoacidic or anacidic patients. Specifically, FIG. 11 (Example 4) shows the dissolution rate of the active drug component API (here, vardenafil) at pH 6.8 (corresponding to the pH of the oral cavity) of the MRP of the present invention. An elution profile in which the elution rate of organic acid (fumaric acid) is plotted against the time axis is also shown. After a lag time of 10 minutes, where both elution rates are both nearly zero, fumaric acid elutes about 90% in 5 minutes, while vardenafil only remains about 60% in 5 minutes. This result indicates that fumaric acid dissolved only a part of the outer gastric film layer. In other words, the dissolution rate of vardenafil is appropriately adjusted by the amount of fumaric acid and the amount of the sustained-release coating layer. In FIG. 11, it can be seen that the elution of vardenafil is controlled by fumaric acid at pH 5.0 to 6.8, and is rapidly eluted under strong acidity at pH 1.2 regardless of fumaric acid.

  The pharmaceutically acceptable organic acid is an acid that provides a pH sufficient to dissolve the outer layer of the gastric film (for example, when the gastric film is aminoalkyl methacrylate copolymer E or polyvinyl acetal diethylaminoacetate, the pH is 5 or less). There is no particular limitation as long as it is pharmaceutically acceptable. For example, fumaric acid, tartaric acid, succinic acid, citric acid, lactic acid, phthalic acid, acetic acid, succinic acid, malonic acid, adipic acid, phytic acid, glutaric acid, maleic acid, malic acid, mandelic acid, ascorbic acid, benzoic acid and toluene Examples thereof include at least one organic acid selected from sulfonic acids and the like, and hydrates thereof. Of these, fumaric acid, tartaric acid, succinic acid and citric acid, and hydrates thereof are preferred, and fumaric acid is particularly preferred from the viewpoint of ease of control and handling due to its moderate acidity and water solubility.

  Organic acids can be granulated themselves or mixed with excipients (eg, crystalline cellulose, lactose, corn starch, etc.) to form organic acid-containing core particles, or outside the core inert core The organic acid-containing core particles may be formed by coating with The size of the organic acid-containing core particles is 10 to 1000 μm, preferably in the range of 100 to 300 μm, for example, about 200 μm.

  When the organic acid-containing layer is coated on the outside of the inert core, the organic acid alone may form the coating layer, but usually a water-soluble polymer binder (for example, hydroxypropylcellulose, piperomellose, methylcellulose, Povidone and the like) and fillers (talc, silica, magnesium stearate, etc.). The organic acid and water-soluble polymer binder are dissolved or dispersed in water, alcohol (eg, ethanol, methanol) or a mixed solvent thereof, and if necessary, the filler is dispersed and applied to the inert core. To form a coating layer. As a coating method, any method capable of coating the particulate pharmaceutical composition, such as a fluidized bed coating apparatus, a rolling fluidized bed coating apparatus, and a centrifugal rolling coating apparatus, may be used. For example, a necessary amount of a liquid containing a coating component such as an organic acid may be sprayed with a spray gun while flowing the inert core particles in a rolling fluidized bed coating apparatus.

The amount of the organic acid is sufficient to dissolve the gastric film, in other words, an amount sufficient to bring the local pH to 5 or less, that is, in stoichiometric amount, it exists in the gastric film. The acid equivalent is preferably equal to or more than that of basic nitrogen. Depending on the desired lag time and the length of the subsequent elution rate, an amount of organic acid greatly exceeding the equivalent amount of basic nitrogen present in the gastric film may be used. The lag time may be in the range of 3-15 minutes, preferably 5-10 minutes (eg 10 minutes). It is preferred that during the lag time, the weakly acidic or basic active ingredient (for example, the basic drug vardenafil) is not substantially released, and after the lag time, the drug release starts rapidly. In the case of vardenafil, after a lag time of 3 to 15 minutes, the release of vardenafil in the gastrointestinal tract immediately matches the elution profile of the commercial product (Levitra®). Can be applied without compromising the bioavailability profile of vardenafil.
When aminoalkyl methacrylate copolymer E (Eudragit (registered trademark) E100 or EPO) is used as the gastric polymer constituting the gastric film and fumaric acid is used as the organic acid, for example, Eudragit (registered trademark) EPO is 100. The fumaric acid may be 2 to 200 parts by weight, preferably 5 to 100 parts by weight, more preferably 15 to 50 parts by weight, for example, 30 parts by weight with respect to parts by weight.

  An active ingredient-containing layer containing a weakly acidic or basic active ingredient (sometimes referred to as a drug-containing layer or a drug layer) is coated on the outside of the organic acid-containing core particles. The active ingredient may be coated alone, but usually contains a water-soluble polymer binder (for example, hydroxypropylcellulose, hypromellose, methylcellulose, povidone, etc.) and a lubricant (talc, magnesium stearate, etc.). It's okay. The drug and water-soluble polymer binder are dissolved or dispersed in water, alcohol (ethanol, methanol) or a mixed solvent thereof. If necessary, the filler is dispersed and applied to the organic acid-containing core particles. Form a drug layer. As a coating method, any method capable of coating the particulate pharmaceutical composition, such as a fluidized bed coating apparatus, a rolling fluidized bed coating apparatus, and a centrifugal rolling coating apparatus, may be used. For example, a required amount of the drug-containing liquid may be sprayed with a spray gun while flowing the organic acid-containing core particles in a rolling fluidized bed coating apparatus.

  The drug used in the present invention may be any drug as long as it is not strongly acidic so that it immediately dissolves the outermost gastric soluble film when contacted with saliva (neutral buffer), that is, weakly acidic It is not particularly limited as long as it is a basic active ingredient and is a therapeutically effective active ingredient or a prophylactically effective active ingredient. The pH of the saturated aqueous solution of the weakly acidic to basic active ingredient is 2.5 to 14, preferably 3.5 to 14. The weakly acidic to basic active ingredient is free or pharmaceutically acceptable. The resulting salt is included. Such pharmaceutically active ingredients include cGMP-specific phosphodiesterase inhibitors, for example, anti-erectile dysfunction drugs such as vardenafil and sildenafil, antituberculosis drugs such as ethambutol hydrochloride, circulatory organs such as varnidipine hydrochloride, nicardipine hydrochloride, indenolol hydrochloride, hydralazine hydrochloride, etc. Antipsychotics such as chlorpromazine hydrochloride, amitriptyline hydrochloride moperone hydrochloride, antiemetics such as ramosetron hydrochloride, granisetron hydrochloride, ondansetron hydrochloride, antiarrhythmic drugs such as propafenone hydrochloride, surface anesthetics such as dibucaine hydrochloride, ranitidine hydrochloride And other drugs for gastrointestinal tract, central nervous system drugs such as tiapride hydrochloride and bifemelane hydrochloride, antibiotics such as ampicillin phthalidyl hydrochloride, and BPH therapeutic agents such as terazosin hydrochloride. As long as the drug is not strongly acidic, either a free form or a pharmaceutically acceptable salt can be used. Moreover, an active ingredient can also be used 1 type or in combination of 2 or more types. These drugs are examples that can be applied to the present invention, and should not be construed as limiting. As an active ingredient to be contained in the particulate pharmaceutical composition of the present invention, a drug that requires timed release and that is required to elute quickly after a lag time, particularly preferably anti-erectile dysfunction such as vardenafil, sildenafil, etc. Among them, vardenafil is preferably used.

  As vardenafil, any of acid adducts such as hydrochloride and organic acid salt, and acid free form can be used. Among these, hydrates (particularly trihydrate) of vardenafil hydrochloride are preferable from the viewpoint of water solubility and stability. The pH of the saturated aqueous solution of vardenafil hydrochloride trihydrate was 4.0.

The compounding amount of the active ingredient in the controlled-release particulate pharmaceutical composition (MRP) of the present invention is usually appropriately selected depending on the type of the active ingredient or the pharmaceutical use (indication). The amount is not particularly limited as long as it is a prophylactically effective amount. It is preferable that the amount is about the same as the particles to be coated because the size and content can be increased. Preferably it is 0.5 to 90% by weight of the whole particulate pharmaceutical composition, more preferably 1.0 to 80% by weight, still more preferably 5.0 to 70% by weight.
Specifically, for example, in the case of the anti-erectile dysfunction drug vardenafil, it is 0.5 to 90% by weight of the whole MRP as vardenafil, more preferably 1 to 70% by weight, still more preferably 5 to 50% by weight, for example, 10 to 20% by weight.
However, the compounding amount of the active ingredient shown here is an example that can be applied to the present invention, and should not be interpreted in a limited manner. The active ingredient-containing layer (drug-containing layer) may preferably contain a polymer binder. Examples of the polymer binder include water-soluble polymers such as hydroxypropylcellulose, hypromellose, methylcellulose, povidone, corn starch, and starch, among which hydroxypropylcellulose is preferable. If necessary, the active ingredient-containing layer may contain a lubricant such as talc or stearic acid (or a salt thereof).
In the present invention, the active ingredient-containing layer-coated particles formed by coating with the active ingredient-containing layer have a size of 10 to 1000 μm, preferably 100 to 300 μm, for example, about 250 μm.

  The controlled release particulate pharmaceutical composition (MRP) of the present invention covers the outside of the active ingredient-containing layer with a gastric film layer. The gastric film layer serves to prevent the active ingredient from being eluted while the particulate pharmaceutical composition is present in the oral cavity and to provide an appropriate lag time. A part or the whole is dissolved by contact with the organic acid eluted from the organic acid-containing core particles by the external liquid (saliva or the like) entering the inside, thereby promoting the elution of the active ingredient. That is, the gastric film layer plays an important role in achieving a desired dissolution profile. Gastric film materials that fulfill these functions are saliva insoluble polymers such as methacrylic acid such as butyl methacrylate / (2-dimethylaminoethyl) methacrylate / methyl methacrylate copolymer and diethylaminoacetate polyvinyl acetal. Acid aminoalkyl copolymers are mentioned. Examples of commercially available polymers include aminoalkyl methacrylate copolymer E (Eudragit (registered trademark) E100 and EPO), polyvinyl acetal diethylaminoacetate (trade name: AEA “Sankyo”), and the like. Aminoalkyl methacrylate copolymer E or polyvinyl acetal diethylaminoacetate is desirable. The gastric film layer may contain other auxiliaries in addition to the gastric material, if necessary. Examples of such auxiliaries include lubricants such as talc and stearic acid metal salts, plasticizers such as macrogol, emulsifiers such as stearic acid, and surfactants such as sodium lauryl sulfate.

  As described above, the gastric film layer of the present invention exhibits the effects of the present invention by dissolving with a local acidic environment created by the organic acid eluted from the organic acid core particles. For example, when a water-insoluble polymer or the like is mixed, it should be noted that the intended purpose of the present invention, that is, rapid release of an effective drug after a predetermined lag time is not achieved. Specifically, for example, a process for masking the bitterness of fast-dissolve (Immediate-release: IR) beads disclosed in US Patent Application Publication No. 2006/0078614 (cited in Japanese translations of PCT publication No. 2009-524698) (Taste mask process) discloses that IR beads are coated with a water-insoluble polymer (eg, ethyl cellulose) alone or in combination with a gastric polymer (eg, Eudragit E100 or EPO). Since a water-insoluble polymer (such as ethyl cellulose) does not dissolve even when it comes into contact with an organic acid, rapid elution of the active ingredient cannot be expected. In fact, paragraphs [0089] to [0092] of JP-T-2009-524698 disclose a taste-masked immediate-release IR bead, but the outer layer is EC-10 (ethylcellulose) / eudragit E100. (Registered trademark) = 50/50 mixed film. According to the knowledge of the inventors, rapid elution of the active ingredient could not be expected.

In the controlled release particulate pharmaceutical composition (MRP) of the present invention, the gastric soluble coating layer acts as a semi-permeable membrane in the neutral state, but when the amount and thickness increase, the external liquid (saliva etc.) from the outside is increased. The invasion is delayed, the elution start of the organic acid from the core particles is delayed, and the dissolution rate of the gastric film layer is reduced. As a result, the elution start time (lag time) of the active ingredient is extended. The amount and thickness of the gastric film layer can be appropriately selected depending on the elution profile of the target active ingredient. The amount of gastric polymer in the gastric coating layer may usually be 5-80% by weight of the total MRP, preferably 10-60% by weight, for example 20-40% by weight. When the gastric film contains a filler such as a plasticizer or a lubricant, the amount of the gastric film layer is usually 5 to 90% by weight, preferably 20 to 80% by weight, for example 30 to 30% by weight of the total amount of MRP. It may be 60% by weight.
The gastric film layer may be formed by applying the above composition once to form a film, but can be divided and applied multiple times. For example, the composition may be applied in two portions. Dividing into multiple times does not have a significant effect on lag time.
In the present invention, the size of the gastric soluble coating layer-coated particles (release controlled particulate pharmaceutical composition (MRP)) formed by coating with a gastric coating layer is 10 to 1000 μm, preferably 100 to 500 μm. For example, it is about 300 μm.

The present invention may preferably have a sustained-release coating layer (SR layer) between the organic acid-containing core particles and the active ingredient-containing layer. Due to the presence of the sustained-release film layer, the penetration rate of external liquid (saliva etc.) from the outside and the release rate of organic acid from the inside are suppressed, and the elution rate after the lag time can be arbitrarily controlled.
That is, in the present invention, a sustained-release film may be coated on the outside of the organic acid-containing layer. The sustained-release coating layer suppresses the invasion of external liquids (saliva etc.) from the outside to the organic acid-containing core particles, and further suppresses the dissolution of dissolved organic acids, resulting in a lag time after the active ingredient lag time. Serves to adjust the dissolution rate. When the coating amount is large, it also contributes to the length of lag time. It also has the effect of clarifying the boundary between the organic acid-containing layer and the active ingredient-containing layer and facilitating precise lag time control. As the sustained-release coating material, a water-insoluble polymer is preferable. Mention may be made of ethylcellulose, methacrylate copolymers and aminoalkyl methacrylate copolymers such as ethyl acrylate / methyl methacrylate copolymers and ethyl acrylate / methyl methacrylate / trimethylammonioethyl methacrylate copolymers. Commercially available water-insoluble polymers include Aquacoat (registered trademark: FMC) ECD, Eudragit NE and Eudragit RS (Evonik), which are aqueous dispersions of ethyl cellulose. Some are on the market.
Other additives may be added to the sustained-release coating material. Examples of such additives include auxiliaries such as talc and plasticizers such as triethyl citrate (SC-60: registered trademark, CBC).

The amount of the sustained-release coating layer is usually 0.1 to 20% by weight, preferably 0.5 to 10% by weight, for example 1 to 5% by weight, based on the total amount of the controlled release particulate pharmaceutical composition (MRP). %.
In the present invention, the size of the sustained-release film-layer-coated particles formed by coating the sustained-release film is 10 to 1000 μm, preferably 100 to 300 μm, for example, about 200 μm.

  In the particulate pharmaceutical composition of the present invention, at least one surface of an organic acid-containing core particle, a sustained-release film layer, and an active ingredient-containing layer (synonymous with “drug-containing layer”) is coated with a seal coat film layer. It may be. It is preferable that the surfaces of the organic acid-containing core particles, the sustained-release coating layer, and the active ingredient-containing layer are respectively coated with a seal coat coating layer. Each layer is completely separated by the presence of the seal coat layer, thereby avoiding interaction (salt formation, etc.), improving production reproducibility, and changing with time (organic acid and active ingredients to other layers). Migration) is suppressed. That is, the objectives of the present invention are (1) suppression of elution of the initial active ingredient in the oral cavity, (2) subsequent rapid release of the active ingredient in the upper GI tract, and (3) lag time control. It can be achieved with high accuracy. The seal coat film layer on the organic acid-containing core particles prevents direct contact between the organic acid and the active ingredient in the active ingredient-containing layer until the organic acid starts to be eluted by the external liquid (saliva etc.) in the oral cavity. Thus, for example, the organic acid forms a salt with a basic active ingredient and has a function of preventing the intended effect (dissolution of the outermost gastric film) from being exhibited. The seal coat on the sustained-release film layer is essential for preventing aggregation during the heat treatment, particularly when a heat treatment after the coating is required like an aqua coat. The seal coat film layer on the active ingredient-containing layer prevents the active ingredient from coming into direct contact with the outermost gastric soluble film and causing chemical and physical changes. Together with these functions, the achievement of the objects (1) to (3) of the present invention is further promoted.

  The seal coat film layer only needs to be capable of separating the respective layers without hindering elution, and can be obtained, for example, by applying and drying a film-forming hydrophilic polymer aqueous solution. A normal hydrophilic polymer can be used as the seal coat film material. For example, hydroxypropylmethylcellulose (HPMC: hypromellose), methylcellulose (MC), hydroxypropylcellulose (HPC), hydroxymethylcellulose (HMC), polyethylene glycol (PEG) 6000 (macrogol 6000), PEG-4000 (macrogol 4000), etc. And a combination of plasticizers. A preferred example is a combination of HPMC and PEG-6000.

The present invention is also a method for producing a controlled release particulate pharmaceutical composition (MRP) comprising:
(I) coating the organic acid-containing layer outside the inert core to form organic acid-containing core particles;
(Ii) a step of coating a sustained-release film on the outside of the organic acid-containing core particles;
(Iii) a step of coating a layer containing a drug on the outside of the sustained-release coating layer; and (iv) a controlled-release particulate form for oral administration by coating the outside of the active ingredient-containing layer with a gastric film. A method for producing a controlled release particulate pharmaceutical composition comprising the step of forming a pharmaceutical composition is provided.

  In the production method, preferably, at least one between the organic acid-containing core particles and the sustained-release coating layer, between the sustained-release coating layer and the active ingredient-containing layer, and between the active ingredient-containing layer and the gastric soluble coating layer. A step of providing a seal coat film layer on one of the layers may be included.

Hereinafter, each process will be described.
In the step (i), an inert core (for example, crystalline cellulose (grain) (Celphere (registered trademark) CP-102 or the like) is fluidized in a rolling fluidized bed granulator while an organic acid (for example, fumaric acid), An aqueous dispersion in which a binder (for example, hydroxypropylcellulose) and a lubricant (for example, talc) are dissolved and dispersed is sprayed from a nozzle and coated on the inert core to form organic acid-containing core particles. The use of an organic solvent is not preferable from the viewpoint of safety and environmental conservation.For example, a fluidized bed granulator, a rolling fluidized bed granulator, a centrifugal rolling granulator or the like is used as the granulator. However, a rolling fluidized bed granulator is preferable for producing fine particles.
The particle size of the inert core may be in the range of 10 to 1000 μm, preferably 100 to 300 μm, for example about 150 μm.
The size of the organic acid-containing core particles is 10 to 1000 μm, preferably in the range of 100 to 300 μm, for example, about 200 μm.
The amount of the organic acid is sufficient to dissolve the gastric film, in other words, an amount sufficient to bring the local pH to 5 or less, that is, in stoichiometric amount, it exists in the gastric film. The acid equivalent is preferably equal to or more than that of basic nitrogen. For example, when fumaric acid is used as the organic acid, Eudragit (registered trademark) EPO is 100 parts by weight, fumaric acid is 2 to 200 parts by weight, preferably 5 to 100 parts by weight, more preferably 15 parts by weight. It may be ˜50 parts by weight, for example 30 parts by weight.

In the step (ii), an aqueous dispersion of an insoluble polymer (for example, ethyl cellulose, cetyl alcohol as a plasticizer, and surface activity) while the organic acid-containing core particles obtained above are fluidized in a rolling fluidized bed granulator. Spray an aqueous dispersion of Aquacoat® ECD-30, which is an aqueous dispersion containing sodium lauryl sulfate as an agent, and a coating aid (eg, triethyl citrate (TEC)) from a nozzle, A sustained release coating is applied. The film is aged by heat treatment to form sustained-release film layer-coated particles.
The amount of the insoluble polymer is, for example, 0.1 to 20% by weight of the total amount of the particulate pharmaceutical composition, preferably 0.5% if expressed by the solid content of Aquacoat (registered trademark) ECD-30. May range from 10 to 10% by weight, more preferably from 1.0 to 5% by weight (where Aquacoat® ECD-30 has a solids content of about 30% by weight).
In the present invention, the size of the sustained-release film-layer-coated particles formed by coating the sustained-release film is 10 to 1000 μm, preferably 100 to 300 μm, for example, about 200 μm.

In the step (iii), while the sustained-release coating layer-coated particles obtained above are flowed in, for example, a rolling fluidized bed granulator, a weakly acidic or basic active ingredient (for example, vardenafil hydrochloride, A trihydrate) -containing solution is sprayed from a nozzle to form an active ingredient-containing layer (synonymous with “drug-containing layer”).
The active ingredient-containing solution is used by dissolving or dispersing the active ingredient in a solvent such as water or alcohol, and contains a water-soluble polymer (for example, hydroxypropylcellulose) and a lubricant (for example, talc) as a binder. Good.
The compounding amount of the active ingredient in the controlled release particulate pharmaceutical composition (MRP) is usually appropriately selected according to the type of the active ingredient or the pharmaceutical use (indication), but is therapeutically effective or prophylactic. The amount is not particularly limited as long as it is effective. Specifically, for example, in the case of the anti-erectile dysfunction drug vardenafil, it is 0.5 to 90% by weight of the whole MRP as vardenafil, more preferably 1 to 70% by weight, still more preferably 5 to 50% by weight, for example, 10 to 20% by weight. The amount of the binder may be in the range of 0.1 to 80 parts by weight, preferably 1.0 to 50 parts by weight, more preferably 5.0 to 20 parts by weight with respect to 100 parts by weight of the active ingredient. . The amount of lubricant is in the range of 0.1 to 80 parts by weight, preferably 1.0 to 50 parts by weight, more preferably 5.0 to 20 parts by weight, based on 100 parts by weight of the active ingredient. Good.
In the present invention, the active ingredient-containing layer-coated particles formed by coating with the active ingredient-containing layer have a size of 10 to 1000 μm, preferably 100 to 300 μm, for example, about 250 μm.

In the step (iv), the active ingredient-containing layer-coated particles obtained above are fluidized in a rolling fluidized bed granulator, and a gastric film material (for example, Eudragit (registered trademark) in a solvent such as water or alcohol). ) A dispersion in which EPO) is dispersed is sprayed from a nozzle to form gastric film-coated particles (controlled release particulate pharmaceutical composition (MRP)). The dispersion containing the gastric film material may contain an emulsifier (for example, stearic acid), a surfactant (for example, sodium lauryl sulfate) and a lubricant (for example, talc).
The amount and thickness of the gastric film layer can be appropriately selected depending on the elution profile of the target active ingredient. The amount of gastric polymer in the gastric coating layer may usually be 5-80% by weight of the total MRP, preferably 10-60% by weight, for example 20-40% by weight. When the gastric film contains a filler such as a plasticizer or a lubricant, the amount of the gastric film layer is usually 5 to 90% by weight, preferably 20 to 80% by weight, for example 30 to 30% by weight of the total amount of MRP. It may be in the range of 60% by weight.
In the present invention, the size of the gastric soluble coating layer-coated particles (release controlled particulate pharmaceutical composition (MRP)) formed by coating with a gastric coating layer is 10 to 1000 μm, preferably 100 to 500 μm. For example, it is about 300 μm.

  The present invention also relates to a disintegration for oral administration, wherein fast-dissolving particles containing no active ingredient are added to the above-mentioned controlled release particulate pharmaceutical composition (MRP) in which the release of the active pharmaceutical ingredient starts rapidly after a predetermined lag time. A particulate particulate composition (ODP) is provided. By adding fast-dissolving particles having an appropriate taste, saliva secretion is promoted and swallowing is facilitated. There is also an effect of facilitating handling as a dosage form.

  The fast-dissolving particles are not particularly limited as long as they have an appropriate taste and have fast solubility, but may be granules containing a sugar alcohol having a sweet taste and a binder. Examples of the sugar alcohol include erythritol, mannitol, sorbitol, maltitol, xylitol, and branched oligosaccharide alcohol, and erythritol and mannitol are preferable. The binder is not particularly limited, and examples thereof include sugars such as lactose, sucrose and glucose, starches such as potato, wheat and corn, celluloses such as hydroxypropylcellulose and hydroxypropylmethylcellulose, and povidone (polyvinylpyrrolidone). Etc. Of these, hydroxypropylmethylcellulose and povidone are preferred.

The present invention also provides a method for producing the above-mentioned collapsible particulate composition (ODP) for oral administration,
(I) coating the organic acid-containing layer outside the inert core to form organic acid-containing core particles;
(Ii) a step of coating a sustained-release film on the outside of the first organic acid-containing core particle;
(Iii) a step of coating a drug-containing layer on the outside of the sustained-release coating layer;
(Iv) coating the outside of the active ingredient-containing layer with a gastric soluble coating to form a controlled release particulate pharmaceutical composition for oral administration; and (v) the controlled release particulate pharmaceutical composition and rapid dissolution. There is provided a method for producing a particulate composition for oral administration, which comprises a step of mixing particles.

Among these steps (i) to (v), steps (i) to (iv) are steps (i) to (iv) in the method for producing a controlled release particulate pharmaceutical composition (MRP). The method for producing a particulate composition for oral administration (ODP) is characterized in that it further comprises step (v).
That is, the method for producing a disintegrating particulate composition for oral administration (ODP) is obtained by applying fast-dissolving particles to a controlled release particulate pharmaceutical composition (MRP) obtained by a production method including steps (i) to (iv). The method further includes a step (v) of mixing. Therefore, in the following, step (v) will be described in detail.

  In the step (v), the controlled release particulate pharmaceutical composition (MRP) obtained in the steps (i) to (iv) and the fast dissolving particles separately prepared are mixed, and the collapsible particulate composition for oral administration. (ODP) is obtained. The fast dissolving particles are prepared by kneading a sugar alcohol (for example, erythritol) and a binder (for example, povidone) with water / ethanol as a solvent using a high shear mixer or the like, and then a cylindrical granulator (Cylindical granulator) or the like is used for granulation, drying and sieving. Furthermore, a fluidizing agent or a lubricant (for example, light anhydrous silicic acid), a charge suppressing agent (for example, talc), and a fragrance as necessary can be added.

  The mixing ratio of the controlled release particulate pharmaceutical composition (MRP) and fast dissolving particles may be usually in the range of 1: 1 to 20, preferably 1: 2 to 10, for example 1: 6. Mixing can be performed using, for example, a cross-rotating mixer. When obtaining a disintegrating particulate composition (ODP) for oral administration by mixing, fluidizing agents or lubricants such as light anhydrous silicic acid, magnesium stearate, talc and sodium stearyl fumarate, and L-menthol, etc. Auxiliaries such as fragrances and flavoring agents can be added. In particular, light silicic acid anhydride as a fluidizing agent or lubricant and addition of L-menthol as a fragrance are preferred. The amount of the fluidizing agent or lubricant added is in the range of 0.05 to 5% by weight, preferably 0.1 to 1% by weight, for example 0.5% by weight of the total amount of ODP. The addition amount of the fragrance or flavoring agent is in the range of 0.005 to 0.5% by weight, preferably 0.01 to 0.1% by weight of the total amount of ODP, for example 0.05% by weight.

  The present invention also provides a seal between at least one of the organic acid-containing core particles and the sustained-release coating layer, between the sustained-release coating layer and the active ingredient-containing layer, and between the active ingredient-containing layer and the gastric soluble coating layer. The manufacturing method of the said collapsible particulate composition for oral administration (ODP) including the process of providing a coat film layer is provided. Preferably, between the organic acid-containing core particles and the sustained-release coating layer, between the sustained-release coating layer and the coating layer containing the active ingredient, and between the coating layer containing the active ingredient and the gastric soluble coating layer Provided is a method for producing the particulate composition for oral administration, which comprises the step of providing a seal coat film layer on all of them. The present invention further provides a method for producing the particulate composition for oral administration, comprising the step of providing a seal coat film layer on the gastric soluble film layer.

  Due to the presence of the seal coat film, the object of the present invention is (1) suppression of elution of the initial active ingredient in the oral cavity, (2) subsequent rapid start of active ingredient release in the upper GI tract, and (3) lag Control of the elution rate after time can be achieved with higher accuracy.

  The step of forming the seal coat film layer will be described, for example, when the seal coat film layer is formed between the organic acid-containing core particles and the sustained-release film layer. A seal coat film layer is formed on the organic acid-containing core particles by spraying an aqueous solution of a film-forming hydrophilic polymer (for example, a combination of hypromellose 2910 and PEG-6000) from a nozzle while flowing in a granulator. can do. The amount of the film-forming hydrophilic polymer is 0.2 to 20 parts by weight, preferably 0.5 to 10 parts by weight, for example, 2 parts by weight with respect to 100 parts by weight of the organic acid-containing core particles. It's okay.

  The production method of the present invention includes a step of mixing saccharides and a binder, and drying after granulation as a method of producing the separately prepared fast dissolving particles. That is, after kneading a sugar alcohol (for example, erythritol) as a saccharide and a binder (for example, povidone) using water, ethanol or the like as a solvent using a high-speed stirring mixer (High shear mixer) or the like, cylindrical granulation is performed. It can be granulated using a machine (Cylinder granulator) or the like, dried using a shelf type dryer (Bed dryer) or the like, and then sieved to make the particle size uniform to obtain fast dissolving particles. The particle size of the fast dissolving particles may be 0.1 to 1.0 mm, preferably 0.1 to 0.3 mm.

  As described above, the present invention also provides a tablet for oral administration, which is obtained by tableting a raw material composition containing the controlled release particulate pharmaceutical composition (MRP) and fast dissolving particles. Provide a lock (ODT). In tablet formation, ODP can be used as it is, or commonly used additives such as excipients, binders, disintegrants and lubricants can be added. If necessary, sugar alcohols (for example, erythritol and mannitol) may be added separately. Tableting can be performed using, for example, a single tableting machine or a rotary tableting machine.

For the controlled release particulate pharmaceutical composition (MRP) of the present invention, a known formulation commonly used in the field can be used, and pharmaceutical additives other than the essential components are pharmaceutically acceptable and additives. If it is various additives used as, it will not restrict | limit in particular. Examples of such pharmaceutical additives include binders, disintegrants, lubricants, flavoring agents, sweeteners, refreshing agents, flavoring agents / fragrances, fragrances, coloring agents, foaming agents, stabilizing (stabilizing) agents, Examples include, but are not limited to, antioxidants, preservatives, pH adjusters, solubilizers, solubilizers, fluidizers, buffers, bases, and excipients.
EXAMPLES The present invention will be specifically described below with reference to examples, but the scope of the present invention is not limited by these examples.

Example 1 [Preparation of controlled release particulate pharmaceutical composition (MRP) without sustained-release coating layer (SR)] (Formulation Example 4)
<1> [(1) Preparation of organic acid-containing layer-coated particles]
Under stirring, an aqueous solution containing 10 g of hydroxypropylcellulose was added and dispersed with 100 g of fumaric acid and 5 g of talc. This dispersion is laterally sprayed on 1000 g of crystalline cellulose (grains) (Celphere® CP-102) using a rolling fluidized bed granulator at an intake temperature of about 60 ° C. and an exhaust temperature of about 28 ° C. To obtain [(1) organic acid-containing layer-coated particles]. The amount of fumaric acid was 10 parts by weight with respect to 100 parts by weight of the cellulose core particles. (Total 1115g)

<2> [(2) Seal coat coating / (1) Preparation of organic acid-containing layer coated particles]
An aqueous solution containing 20 g of hydroxypropylmethylcellulose (hypromellose) and 5 g of polyethylene glycol (Macrogol 6000) was used for the (1) organic acid-containing layer-coated particles obtained above using a rolling fluidized bed granulator. Side spraying was performed at an intake temperature of about 85 ° C. and an exhaust temperature of about 42 ° C. to obtain [(2) seal coat coating / (1) organic acid-containing layer coated particles]. (Total 1140g)

<3> [(3) Active ingredient-containing layer coating / (2) Seal coat coating / (1) Preparation of organic acid-containing layer-coated particles]
While stirring, an aqueous solution containing 32 g of hydroxypropylcellulose was added and dispersed with 320 g of vardenafil hydrochloride trihydrate (manufactured by BayerHC) and 16 g of talc. This dispersion was applied to 456 g of [(2) seal coat coating / (1) organic acid-containing layer coated particles] obtained above, using a rolling fluidized bed granulator, with an intake air temperature of about 55 ° C., exhaust gas Side spraying was performed at a temperature of about 28 ° C. to obtain [(3) active ingredient-containing layer coating / (2) seal coat coating / (1) organic acid-containing layer coated particles]. (Total 824g)

<4> [(4) Seal coat coating / (3) Active ingredient-containing layer coating / (2) Seal coat coating / (1) Preparation of organic acid-containing layer-coated particles]
An aqueous solution containing 16 g of hydroxypropylmethylcellulose (hypromellose) and 4 g of polyethylene glycol (Macrogol 6000) was obtained above [(3) Active ingredient-containing layer coating / (2) Seal coat coating / (1) Organic acid-containing layer [Coated particles] are sprayed laterally at an intake air temperature of about 85 ° C. and an exhaust temperature of about 40 ° C. using a rolling fluidized bed granulator, [(4) seal coat coating / (3) active ingredient containing layer Coating / (2) Seal coat coating / (1) Organic acid-containing layer coated particles]. (Total 844g)

<5> [(5) Gastric soluble coating / (4) Seal coat coating / (3) Active ingredient-containing layer coating / (2) Seal coat coating / (1) Preparation of organic acid-containing layer coated particles]
Under stirring, an aqueous solution containing 20 g of sodium lauryl sulfate was added and dispersed with 200 g of aminoalkyl methacrylate copolymer E (Eudragit (registered trademark) EPO) and 30 g of stearic acid. Subsequently, 70 g of talc was added with stirring to prepare a dispersion. This dispersion was rolled against 320 g of [(4) seal coat coating / (3) active ingredient-containing layer coating / (2) seal coat coating / (1) organic acid-containing layer coated particles] obtained above. Using a fluidized bed granulator, the spray is laterally sprayed at an intake temperature of about 45 ° C. and an exhaust temperature of about 28 ° C., which is the controlled release particulate pharmaceutical composition (MRP) of the present invention [(5) gastric soluble film Coating / (4) Seal coat coating / (3) Active ingredient-containing layer coating / (2) Seal coat coating / (1) Organic acid-containing layer coated particles] (formulation example 4: see Table 2). The coating amount of the gastric film is 100 weight parts per 100 weight parts of [(4) seal coat coating / (3) active ingredient-containing layer coating / (2) seal coat coating / (1) organic acid-containing layer coated particles]. Was part. (Total 640 g). The average particle size of the obtained MRP particles was 267 μm, and the content of the active ingredient vardenafil was about 16% by weight.
Formulation examples 1, 2, and 3 having no sustained release coating layer (SR) can also be produced in the same manner as in Example 1.

Example 2 [Preparation of controlled release particulate pharmaceutical composition (MRP) having sustained-release coating layer (SR)] (Formulation Example 10)
<1> [(1) Preparation of organic acid-containing layer-coated particles]
Under stirring, an aqueous solution containing 20 g of hydroxypropylcellulose was added and dispersed with 200 g of fumaric acid and 10 g of talc. This dispersion is laterally sprayed on 1000 g of crystalline cellulose (grain) (Celphere® CP-102) using a tumbling fluidized bed granulator at an intake temperature of about 65 ° C. and an exhaust temperature of about 30 ° C. To obtain [(1) organic acid-containing layer-coated particles]. The amount of fumaric acid was 20 parts by weight with respect to 100 parts by weight of the cellulose core particles. (Total 1230g)

<2> [(2) Seal coat coating / (1) Preparation of organic acid-containing layer coated particles]
An aqueous solution containing 24 g of hydroxypropylmethylcellulose (hypromellose) and 6 g of polyethylene glycol (Macrogol 6000) was used for (1) organic acid-containing layer-coated particles obtained above using a rolling fluidized bed granulator. Side spraying was performed at an intake temperature of about 80 ° C. and an exhaust temperature of about 42 ° C. to obtain [(2) seal coat coating / (1) organic acid-containing layer coated particles]. (Total 1260g)

<3> [(3) Sustained release film coating / (2) Seal coat coating / (1) Preparation of organic acid-containing layer coated particles]
An aqueous dispersion containing 400 g of ethylcellulose aqueous dispersion (Aquacoat (registered trademark) ECD-30) (solid content 120 g) and 15 g of triethyl citrate was obtained as above [(2) Seal coat coating / (1) organic acid Contained particles] 450 g is subjected to side spraying at an intake temperature of about 75 ° C. and an exhaust temperature of about 32 ° C. using a rolling fluidized bed granulator, [(3) active ingredient containing layer coating / (2) Seal coat coating / (1) Organic acid-containing layer-coated particles] was obtained. The coating amount of the sustained release film was 30 parts by weight with respect to 100 parts by weight of [(2) Seal coat coating / (1) Organic acid-containing coated particles]. (Total 585g)

<4> [(4) Seal coat coating / (3) Sustained release film coating / (2) Seal coat coating / (1) Preparation of organic acid-containing layer coated particles]
An aqueous solution containing 12 g of hydroxypropylmethylcellulose (hypromellose) and 3 g of polyethylene glycol (Macrogol 6000) was obtained above [(3) Sustained release film coating / (2) Seal coat coating / (1) Organic acid-containing layer The coated particles were sprayed sideways at an intake temperature of about 80 ° C. and an exhaust temperature of about 40 ° C. using a rolling fluidized bed granulator. After spraying is completed, the film is matured by heat treatment for 90 minutes at an intake air temperature of 85 ° C. (exhaust temperature is expected), [(4) Seal coat coating / (3) Sustained release film coating / (2) Seal coat coating / (1) Organic acid-containing layer-coated particles]. (Total 600g)

<5> [(5) Active ingredient-containing layer coating / (4) Seal coat coating / (3) Sustained release coating / (2) Seal coat coating / (1) Preparation of organic acid-containing layer coated particles]
While stirring, an aqueous solution containing 20 g of hydroxypropylcellulose was added and dispersed with 200 g of vardenafil hydrochloride trihydrate (manufactured by BayerHC) and 10 g of talc. This dispersion was rolled against 420 g of [(4) seal coat coating / (3) sustained release coating / (2) seal coat coating / (1) organic acid-containing layer coated particles] obtained above. Using a fluidized bed granulator, side spraying is performed at an intake temperature of about 50 ° C. and an exhaust temperature of about 28 ° C. [[5) Active ingredient-containing layer coating / (4) Seal coat coating / (3) Sustained release coating Coating / (2) Seal coat coating / (1) Organic acid-containing layer coated particles]. (Total 650 g)

<6> [(6) Seal coat coating / (5) Active ingredient-containing layer coating / (4) Seal coat coating / (3) Sustained release coating / (2) Seal coat coating / (1) Organic acid-containing layer Preparation of coated particles]
An aqueous solution containing 12 g of hydroxypropylmethylcellulose (hypromellose) and 3 g of polyethylene glycol (Macrogol 6000) was obtained above [(5) Active ingredient-containing layer coating / (4) Seal coat coating / (3) Sustained release coating Coating / (2) seal coat coating / (1) organic acid-containing layer coated particles] using a tumbling fluidized bed granulator and side spraying at an intake air temperature of about 85 ° C. and an exhaust temperature of about 42 ° C. [(6) Seal coat coating / (5) Active ingredient containing layer coating / (4) Seal coat coating / (3) Sustained release coating coating / (2) Seal coat coating / (1) Organic acid containing layer coating particles ] Was obtained. (Total 665g)

<7> [(7) Gastric soluble coating / (6) Seal coat coating / (5) Active ingredient-containing layer coating / (4) Seal coat coating / (3) Sustained release coating coating / (2) Seal coat coating / (1) Preparation of organic acid-containing layer-coated particles]
While stirring, an aqueous solution containing 15 g of sodium lauryl sulfate was added and dispersed by adding 150 g of aminoalkyl methacrylate copolymer E (Eudragit (registered trademark) EPO) and 22.5 g of stearic acid. Subsequently, 52.5 g of talc was added with stirring to prepare a dispersion. This dispersion was obtained as described above [(6) Seal coat coating / (5) Active ingredient-containing layer coating / (4) Seal coat coating / (3) Sustained release film coating / (2) Seal coat coating / ( 1) Organic acid-containing layer-coated particles] With respect to 320 g, using a rolling fluidized bed granulator, side spraying is performed at an intake temperature of about 42 ° C. and an exhaust temperature of about 27 ° C. It is a pharmaceutical composition (MRP) [(7) gastric film coating / (6) seal coat coating / (5) active ingredient-containing layer coating / (4) seal coat coating / (3) sustained release film coating / (2) Seal coat coating / (1) Organic acid-containing layer-coated particles] (Formulation Example 10: Table 4) were obtained. The coating amount of the gastric film was [(6) Seal coat coating / (5) Active ingredient-containing layer coating / (4) Seal coat coating / (3) Sustained release film coating / (2) Seal coat coating / (1 ) Organic acid-containing layer-coated particles] 75 parts by weight with respect to 100 parts by weight. (Total 560 g). The average particle diameter of the obtained MRP particles was 276 μm, and the content of the active ingredient vardenafil was about 14% by weight.
The following formulation examples 5-9, 11-18 and 20 having a sustained-release coating layer (SR) can also be produced in the same manner as in Example 2.

Comparative Example 1 [Particle preparation without organic acid-containing layer] (Comparative preparation example 4)
The <1> [(1) Preparation of organic acid-containing layer-coated particles] step and <2> [(2) Seal coat coating / (1) Preparation of organic acid-containing layer-coated particles] step in Example 1 were omitted. Except for the above, a particulate pharmaceutical composition was prepared according to Example 1. That is, the obtained particulate pharmaceutical composition has a four-layer structure consisting of [(4) gastric soluble film coating / (3) seal coat coating / (2) active ingredient-containing layer coating / (1) inert core particles]. There is no organic acid-containing layer. The coating amount of the gastric film was 32.4 parts by weight with respect to 100 parts by weight of [(3) Seal coat coating / (2) Active ingredient-containing layer coating / (1) Inactive core particles].
The average particle size of the obtained [(4) gastric film coating / (3) seal coat coating / (2) active ingredient containing layer coating / (1) inert core particles] was 237 μm, and the content of the active ingredient vardenafil was About 28% by weight (Comparative formulation example 4: see Table 1).
Comparative Formulation Example 3, which is a particle formulation without an organic acid-containing layer, can also be produced in the same manner as Comparative Example 1. Further, Comparative Formulation Examples 1 and 2 were also in accordance with Comparative Example 1 and Example 2 above, (5) Seal coat coating (overcoat) (4) Sustained release film coating / (3) Seal coat coating / (2) Each step can be appropriately selected and manufactured in the order of active ingredient containing layer coating / (1) inert core particles.

  Example 3 [Dissolution profile of active ingredient (Vardenafil) from controlled release particulate pharmaceutical composition (MRP: Comparative Formulation Examples 1-4 and Formulation Examples 1-18 and 20)]

  For the controlled release particulate pharmaceutical composition (MRP) obtained in Examples 1 and 2, and Comparative Example 1 and the particulate pharmaceutical composition obtained according to them, the dissolution profile of the active ingredient (Vardenafil) was measured. did.

The dissolution test was performed according to the paddle method (apparatus 2) of the Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method. That is, 900 mL of a test solution adjusted to a predetermined pH is placed in a stirring layer in a constant temperature water bath set at 37 ° C., and an amount of MRP corresponding to 10 mg of vardenafil is dispersed. Sampling the paddle at 50 rpm or 100 rpm, sampling every predetermined time, and elution of vardenafil by the Japanese Pharmacopoeia General Test Method 2.24 UV-Vis Absorbance Measurement Method or 2.01 Liquid Chromatography for the filtrate through the membrane filter The amount was monitored (the amount of fumaric acid released was also monitored in liquid chromatography). The obtained results are shown in FIGS. 4 to 15, Control is a commercially available product (Levitra (registered trademark) 10 mg). 1-4 and Ex. 1 to 18 and 20 represent Comparative Formulation Examples 1 to 4 and Formulation Examples 1 to 18 and 20, respectively.
Further, in Table 8-15 also be displayed with 1% elution time MRP (t1% [min] _{(t 1%} [min]);. To lag time is defined "1% dissolution of the present invention . it represents the required time "until) and after 15 min dissolution rate (d15 min [%] (sometimes indicated as d _{15 min} [%].); a is an index of the dissolution rate after lag time). Show. In Tables 8 to 15, Control is a commercially available product (Levitra (registered trademark) 10 mg).
The results of these elution profiles are summarized below.
Comparative Formulation Examples 1 and 2: By applying a sustained-release film on the outside of the active ingredient layer, a short lag time is generated (Comparative Formulation Example 1), but after the lag time is increased as the film is thickened to extend the lag time. Elution is suppressed. The mixed-release film of the sustained-release film and the water-soluble polymer has essentially the same problem as the simple-release film (Comparative Formulation Example 2).
Comparative formulation examples 3 and 4: By applying a gastric film on the outside of the active ingredient layer, elution at the pH in the oral cavity (pH 6.8) can be suppressed. However, if the film is thick, it does not dissolve almost even after a long time (Comparative Formulation Example 4). If the film is thin, acceleration of dissolution based on incomplete film (short lag time) is observed, but subsequent release Is incomplete and reproducibility cannot be expected at all (Comparative Preparation Example 3).
Formulation example 1-4 (Example without sustained release film): The elution rate after the lag time can be adjusted by adjusting the thickness of the gastric soluble film and the amount of fumaric acid (pH 6.8). In addition, it is quick release when acidic.
Formulation Example 5-10 (Example with Sustained Release Film): The dissolution rate after the lag time can be adjusted by the thickness of the sustained release film (pH 6.8). Moreover, it is an immediate release when it is acidic.
Formulation Examples 11-18 and 20: Whether the sustained-release film is an aqueous dispersion of ethyl cellulose (Aquacoat ECD-30) or an ethyl acrylate / methyl methacrylate copolymer dispersion (Eudragit NE30D), the dissolution profile is precisely controlled. That is, it is suggested that a semipermeable membrane is applicable. Moreover, it can be seen from Formulation Example 16 that if necessary, the surface of the controlled-release particulate pharmaceutical composition (MRP) can be modified. For example, even when 10% of erythritol is coated, the dissolution characteristics are maintained.

Example 4 [Comparison of Elution Profiles of Active Ingredient (Vardenafil) and Fumaric Acid from Controlled Release Particulate Pharmaceutical Composition (MRP: Formulation Example 12)]
Controlled release particulate pharmaceutical composition prepared according to Example 2 [(7) gastric film coating / (6) seal coat coating / (5) active ingredient containing layer coating / (4) seal coat coating / (3 The elution profiles of vardenafil and fumaric acid were simultaneously measured according to Example 3 using)) slow release film coating / (2) seal coat coating / (1) organic acid-containing layer coated particles] (MRP).

  The layer structure of MRP used for the measurement and the composition of each layer are Formulation Example 12 in Table 4, and the dissolution profile is as shown in FIG. In the figure, Ex. 12 represents Formulation Example 12, and FA at pH 1.2, FA at pH 5.0 and FA at pH 6.8 are respectively fumaric acid at pH 1.2, fumaric acid at pH 5.0 and fumaric acid at pH 6.8. Represents.

  The following can be seen from the results of the elution profile. That is, in Formulation Example 12, weak acid to neutral (pH 5 or higher), the lag time coincides (synchronizes) with the start of organic acid release, and the organic acid is the outermost layer (Eudragit E) according to the controlled release rate. Elution of the active ingredient starting with the dissolution of a part or the whole of the solution and increasing the surface area when exposed to the external liquid begins. In addition, since the dissolution proceeds from the outermost layer in acidic (pH 1.2), the active ingredient is eluted prior to the release of the organic acid (rapid release).

Example 5
[Preparation of non-active fast dissolving particles]
980 g of erythritol and 20 g of povidone were put into a high-speed stirring granulator, and 75% ethanol was added as a wetting agent and kneaded. This kneaded product was granulated using a cylindrical granulator and dried with a shelf dryer. The particle size was adjusted with a net type granulator to obtain inactive fast dissolving particles.

[Preparation of particulate composition for oral administration (ODP)]
69.8 g of [Release Controlled Particulate Pharmaceutical Composition Having Sustained Release Film Layer (Formulation Example 12)] obtained according to Example 2 and 930.2 g of [Inactive Fast Dissolving Particles] obtained above were mixed. Then, 1000 g of an oral administration particulate composition (ODP) was prepared (Formulation Example 19). The content of the active ingredient vardenafil was about 1% by weight.
A particulate composition for oral administration (ODP) of Preparation Examples 22-24 can also be produced in the same manner as in Example 5.

[Preparation of Orally Disintegrating Tablets (ODT)]
In the orally disintegrating tablet (ODT) of Preparation Example 21, a fluidizing agent (light anhydrous silicic acid) was added to the controlled release particulate pharmaceutical composition (MRP) (Formulation Example 10) produced in Example 2 (Formulation Example) 20), [Inactive fast-dissolving particles] and a lubricant (sodium stearyl fumarate), and then compression-molded to obtain a curing treatment described in Japanese Patent No. 2919771.

Example 6 [Elution profile of active ingredient (Vardenafil) from particulate composition for oral administration]
Using the particulate composition for oral administration (ODP) and the orally disintegrating tablet (ODT) prepared according to Example 5 or according thereto, the dissolution profile of the active ingredient (Vardenafil) was measured in the same manner as in Example 3. The obtained results are shown in FIGS.

  In FIGS. 12 and 13, Control is a commercially available product (Levitra (registered trademark) 10 mg), and in FIG. 16, Control is a commercially available product (Levitra (registered trademark) 20 mg), in FIGS. Ex. 12, 19, 21, 22, 23, and 24 represent Formulation Examples 12, 19, 21, 22, 23, and 24, respectively.

“Ex. 19, 6M” in FIG. 19 represents a sample of 19 orally administered particulate composition (ODP) particles packaged with a desiccant and stored under accelerated test conditions (40 ° C./75% RH (relative humidity)) for 6 months. Ex. The dissolution characteristics of 19,6M particulate composition for oral administration (ODP) are Ex. Little change from the 19 orally administered particulate composition (ODP) suggests long-term stability.
Tables 14 to 16 show 1% elution time of ODP and ODT (t1% [min]; “time required for 1% elution” as defined by the lag time of the present invention) and elution rate after 15 minutes ( d15 minutes [%]; index of elution rate after lag time). In Tables 14 to 15, Control is a commercially available product (Levitra (registered trademark) 10 mg), and in Table 16, Control is a commercially available product (Levitra (registered trademark) 20 mg). "19,6M" means that the particulate composition for oral administration (ODP) particles of Preparation Example 19 are packaged with a desiccant and stored for 6 months under accelerated test conditions (40 ° C / 75% RH (relative humidity)). Represents the sample.

  Sweet ingredients that promote the secretion of saliva (fast-dissolving granules prepared separately), such as the particulate compositions for oral administration (ODP) or orally disintegrating tablets (ODT) of Preparation Examples 19, 21, 22, 23 and 24, necessary Depending on the condition, adding a fluidizing agent, lubricant or fragrance, etc. to sachet or tablet, it is convenient for taking and carrying, while maintaining dissolution properties and good stability (acceleration for 6 months) Test).

  The formulations of Comparative Preparation Examples 1 to 4 and Preparation Examples 1 to 24 are shown in Tables 1 to 7 below, and the 1% elution time (t1% [min]) and the elution rate after 15 minutes (d15 minutes [%]) are shown below. Are shown in Tables 8-16.

  Table 1 [Particle preparation without organic acid-containing layer: Comparative preparation examples 1 to 4]

  Table 2 [Release Controlled Particulate Pharmaceutical Composition (MRP) Without Sustained Release Film Layer (SR): Formulation Examples 1-4]

  Table 3 [Release Controlled Particulate Pharmaceutical Composition (MRP) Having Sustained Release Coating Layer (SR): Formulation Examples 5 to 8]

  Table 4 [Release Controlled Particulate Pharmaceutical Composition (MRP) Having Sustained Release Coating Layer (SR): Formulation Examples 9-12]

  Table 5 [Release Controlled Particulate Pharmaceutical Composition (MRP) Having Sustained Release Coating Layer (SR): Formulation Examples 13 to 16]

  Table 6 [Release Controlled Particulate Pharmaceutical Composition (MRP) Having Sustained Release Coating Layer (SR) or Particulate Composition for Oral Administration (ODP) Using MRP: Production Examples 17 to 20]

  Table 7 [Particulate composition for oral administration (ODP) or orally disintegrating tablet (ODT) using controlled release particulate pharmaceutical composition (MRP) having sustained-release coating layer (SR): Production Examples 21 to 21] 24]

  Table 8 [Control (commercially available Levitra (registered trademark) tablets 10 mg) and MRP at pH 1.2, 1% elution time (t1% [min]) and elution rate after 15 min (d15 min [%]): equivalent to vardenafil 10 mg Volume dispersion, stirring paddle at 50 rpm, using 900 ml test solution: corresponding to FIG. ]

  Table 9 [Control (commercially available Levitra (registered trademark) tablets 10 mg) and MRP at pH 1.2, 1% elution time (t1% [min]) and elution rate after 15 min (d15 min [%]): equivalent to vardenafil 10 mg Volume dispersion, stirring paddle at 50 rpm, using 900 ml test solution: corresponding to FIGS. ]

  Table 10 [Control (commercial product Levitra (registered trademark) tablets 10 mg) and MRP at 1% elution time (t1% [min]) at pH 6.8 and elution rate after 15 min (d15 min [%]): equivalent to vardenafil 10 mg Volume dispersion, stirring paddle at 50 rpm, using 900 ml test solution: corresponding to FIG. ]

  Table 11 [Control (commercially available Levitra (registered trademark) tablets 10 mg) and MRP at 1% elution time (t1% [min]) at pH 6.8 and elution rate after 15 min (d15 min [%]): equivalent to vardenafil 10 mg Volume dispersion, stirring paddle at 50 rpm, using 900 ml test solution: corresponding to FIGS. ]

  Table 12 [Control (commercially available Levitra (registered trademark) tablets 10 mg) and MRP 1% elution time (t1% [min]) at pH 6.8 and elution rate after 15 min (d15 min [%]): equivalent to vardenafil 10 mg Volume dispersion, stirring paddle at 100 rpm, using 900 ml test solution: corresponding to FIG. ]

  Table 13 [MRP pH 1.2, 5.0 and 6.8 at 1% elution time (t1% [min]) and elution rate after 15 min (d15 min [%]): Vardenafil equivalent to 10 mg dispersion, paddle Stirring at 50 rpm, using 900 ml test solution: corresponding to FIG. ]

  Table 14 [Control (commercially available Levitra (registered trademark) tablets 10 mg), MRP, ODP and ODT at 1% elution time (t1% [min]) at pH 1.2 and elution rate after 15 min (d15 min [%]) : Vardenafil 10 mg equivalent dispersion, paddle stirring at 50 rpm, 900 ml test solution used: corresponding to FIGS. ]

  Table 15 [Control (commercially available Levitra (registered trademark) tablets 10 mg), MRP, ODP and ODT at 1% elution time (t1% [min]) at pH 6.8 and elution rate after 15 min (d15 min [%]) : Vardenafil 10 mg equivalent dispersion, paddle agitation at 50 rpm, 900 ml test solution used: corresponding to FIGS. ]

  Table 16 [Control (commercially available Levitra (registered trademark) tablets 20 mg) and 1% dissolution time (t1% [min]) and dissolution rate after 15 minutes (pH 15 min [%]) of ODP: equivalent to 20 mg of vardenafil Volume dispersion, stirring paddle at 100 rpm, using 900 ml test solution: corresponding to FIG. ]

  The present invention is a weakly acidic or basic active ingredient typified by vardenafil, has a sufficiently long lag time, and can release the active ingredient promptly after the lag time, and the characteristics / objectives of the active ingredient / formulation Accordingly, the present invention provides a controlled-release particulate pharmaceutical composition capable of arbitrarily controlling the length of lag time and the subsequent dissolution rate, and an intraoral rapidly disintegrating particle or tablet containing the composition.

Claims (28)

  A multi-layered particulate pharmaceutical composition for oral administration, comprising at least a core particle containing a pharmaceutically acceptable organic acid, and a weakly acidic or basic active ingredient on the outside of the organic acid-containing core particle A controlled release particulate pharmaceutical composition comprising an active ingredient-containing layer and a gastric soluble coating layer outside the active ingredient-containing layer.   2. Controlled release according to claim 1, characterized in that the release of the active ingredient from the pharmaceutical composition does not substantially occur in the oral cavity and then occurs rapidly in the upper gastrointestinal tract. Type particulate pharmaceutical composition.   3. The controlled release particulate pharmaceutical composition according to claim 1 or 2, wherein the release of the active ingredient starts when the organic acid dissolves the gastric film layer.   The controlled-release particulate pharmaceutical composition according to any one of claims 1 to 3, further comprising a sustained-release film layer between the organic acid-containing core particles and the active ingredient-containing layer.   The controlled release particulate pharmaceutical composition according to any one of claims 1 to 4, wherein the organic acid-containing core particle is a particle obtained by coating an organic acid-containing layer on the outside of an inert core.   The seal coat film layer is coated on at least one surface of the organic acid-containing core particles, the sustained-release film layer, the active ingredient-containing layer, and the gastric soluble film layer according to any one of claims 1 to 5. Controlled release particulate pharmaceutical composition.   The controlled release particulate pharmaceutical composition according to any one of claims 1 to 6, wherein the active ingredient is vardenafil hydrochloride hydrate.   The controlled release type according to any one of claims 1 to 7, wherein the organic acid is at least one selected from the group consisting of fumaric acid, tartaric acid, succinic acid and citric acid, and hydrates thereof. Particulate pharmaceutical composition.   The controlled release particulate pharmaceutical composition according to any one of claims 1 to 8, wherein the organic acid is fumaric acid.   The inert core is at least one selected from the group consisting of crystalline cellulose granules, sucrose / starch spherical granules, purified sucrose spherical granules, lactose / crystalline cellulose spherical granules, and mannitol spherical granules. The controlled release particulate pharmaceutical composition according to one.   The controlled release particulate pharmaceutical composition according to any one of claims 5 to 10, wherein the inert core is a crystalline cellulose granule.   The controlled release particulate pharmaceutical composition according to any one of claims 1 to 11, wherein the gastric film layer contains at least one selected from the group consisting of aminoalkyl methacrylate copolymer E and polyvinyl acetal diethylaminoacetate. .   The controlled release particulate pharmaceutical composition according to any one of claims 6 to 12, wherein the seal coat contains at least one selected from the group consisting of hypromellose and methylcellulose.   The controlled release particulate pharmaceutical composition according to any one of claims 4 to 13, wherein the sustained-release coating layer contains ethyl cellulose or ethyl acrylate / methyl methacrylate copolymer. A method for producing a controlled release particulate pharmaceutical composition according to any one of claims 1 to 14,
(I) coating the organic acid-containing layer outside the inert core to form organic acid-containing core particles;
(Ii) a step of coating the organic acid-containing core particles with a sustained-release coating (iii) a step of coating a layer containing an active ingredient on the outside of the sustained-release coating layer, and (iv) the active component A method for producing a controlled release particulate pharmaceutical composition comprising the step of coating the outer side of a containing layer with a gastric soluble film to form a controlled release particulate pharmaceutical composition for oral administration.   A seal coat film layer is provided between at least one of the organic acid-containing core particles and the sustained-release film layer, between the sustained-release film layer and the active ingredient-containing layer, and between the active ingredient-containing layer and the gastric soluble film layer. The manufacturing method of Claim 15 including a process.   15. A disintegrating particulate composition for oral administration comprising the controlled release particulate pharmaceutical composition according to any one of claims 1 to 14 and a fast dissolving particle containing no active ingredient.   The disintegrating particulate composition for oral administration according to claim 17, wherein the fast dissolving particles comprise a sugar alcohol and a binder.   The disintegrating particulate composition for oral administration according to claim 18, wherein the sugar alcohol is erythritol.   20. A disintegrating particulate composition for oral administration according to claim 18 or 19, wherein the binder is povidone or hydroxypropylcellulose. The disintegrating particulate composition for oral administration according to any one of claims 17 to 20, further comprising a fluidizing agent or lubricant and / or a fragrance. A method for producing a disintegrating particulate composition for oral administration according to any one of claims 17-21,
(I) coating the organic acid-containing layer outside the inert core to form organic acid-containing core particles;
(Ii) a step of coating a sustained-release coating on the outside of the organic acid-containing core particles (iii) a step of coating a layer containing an active ingredient on the outside of the sustained-release coating layer;
(Iv) coating the outside of the active ingredient-containing layer with a gastric soluble coating to form a controlled release particulate pharmaceutical composition for oral administration; and (v) the controlled release particulate pharmaceutical composition and fast dissolution A method for producing a particulate composition for oral administration, comprising a step of mixing particles and, if necessary, a fluidizing agent or lubricant and / or a fragrance.   A seal coat film layer is provided between at least one of the organic acid-containing core particles and the sustained-release film layer, between the sustained-release film layer and the active ingredient-containing layer, and between the active ingredient-containing layer and the gastric soluble film layer. The manufacturing method of Claim 22 including a process.   24. A method for producing a disintegrating particulate composition for oral administration, comprising the steps of producing fast-dissolving particles by mixing sugar alcohol, a binder and a wetting agent, granulating and then drying. Manufacturing method.   An orally disintegrating tablet, which is obtained by tableting the particulate composition for oral administration according to any one of claims 17 to 21.   15. The controlled release particulate medicine according to any one of claims 1 to 14, wherein the weakly acidic or basic active ingredient is not substantially released for 3 to 15 minutes after oral administration, and then the release starts rapidly. Composition.   The disintegrating particles for oral administration according to any one of claims 17 to 21, wherein the weakly acidic or basic active ingredient is not substantially released for 3 to 15 minutes after oral administration, and then the release starts rapidly thereafter. Composition.   26. The orally disintegrating tablet according to claim 25, wherein the weakly acidic or basic active ingredient is not substantially released for 3 to 15 minutes after oral administration, and then the release starts rapidly.

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