KR101639692B1 - Orally dispersible, multiple-unit pharmaceutical composition comprising two or more active ingredients - Google Patents

Abstract

The present invention relates to an oral fast-disintegrating multi-unit pharmaceutical composition comprising two or more active ingredients and consisting of a plurality of unit units. Since the pharmaceutical composition of the present invention has the same degree of drug release as compared with a single preparation, a pharmacological effect equivalent to that of a single preparation can be expected. It is expected that dosage compliance will be improved because the number of dosage forms taken is reduced. Particularly, according to the present invention, since the second layer coating on the enteric layer is smoothly applied on the enteric layer, the problem of coating the enteric layer on the enteric layer can be solved.

Description

ORALY DISPERSIBLE, MULTIPLE-UNIT PHARMACEUTICAL COMPOSITION COMPRISING TWO OR MORE ACTIVE INGREDIENTS,

The present invention relates to an oral fast-disintegrating multi-unit pharmaceutical composition comprising two or more active ingredients and consisting of a plurality of unit units. More specifically, an inert core; A first drug layer coated on the inert core; A pharmaceutical composition comprising a plurality of unit units comprising a second drug layer coated on a first drug layer, wherein the first drug layer is intended to achieve release of the first active ingredient and the second drug layer is intended to achieve release ≪ / RTI > The present invention relates to a pharmaceutical composition intended to achieve effective intracellular release. The unit unit of the pharmaceutical composition of the present invention may further comprise a release coating as a means for causing the first active ingredient to be released from the first drug layer and may further comprise a pharmacological property of the first active ingredient, It is possible to additionally include an enteric coating layer between the first drug layer and the second drug layer in consideration of the behavior. In addition, the second drug layer contains an alkalizing agent so that the second drug layer can be coated on the enteric coating layer in an excellent and efficient manner.

As means for incorporating two or more active ingredients into one pharmaceutical composition, it is possible to prepare granules by a conventional granulation method by simply mixing the active ingredients, and then to form tablets or capsules, or granules containing the respective active ingredients separately And then mixed to prepare a suitable formulation.

However, when a plurality of active ingredients contained in one formulation have different emission patterns or the emission pattern needs to be adjusted so as to achieve a specific purpose, they are simply mixed into one granule or a separate granule to prepare a pharmaceutical composition , It will not be able to achieve the emission pattern appropriate for each active ingredient. For example, if one active ingredient should consist of a sustained release, the other active ingredient should be constituted by immediate release, or one active ingredient should be enteric coated and the other active ingredient should not As is the case, when different release patterns are required, more sophisticated formulation techniques are required to construct this one formulation. In particular, in order to formulate a formulation having two or more effective components as described above, it is necessary to develop a special formulation that is different from conventional formulation techniques, assuming that the formulation is to be rapidly disintegrated in the oral cavity.

In accordance with this need, Korean Patent Laid-Open Publication No. 2012-31002 discloses a pharmaceutical composition comprising a plurality of non-opioid analgesic / opiate analgesic drug-containing microparticles, which comprises (a) a non-opioid analgesic drug Core; (b) a first coating distributed on the center, comprising an opiate analgesic drug; And (c) a second coating distributed over the center, comprising a water-insoluble polymer.

Korean Patent Laid-Open Publication No. 2011-113940 discloses a pharmaceutical composition comprising an enteric sustained-release pellet part and a fast-disintegrating part containing tamsulosin or a pharmaceutically acceptable salt thereof as an active ingredient, wherein an enteric-sustained-release pellet part (a ) A pellet core; (b) a drug coating layer coated on the pellet core with tamsulosin or a pharmaceutically acceptable salt thereof; (c) a sustained-release coating layer coated on the drug coating layer with a water-insoluble polymer, a water-soluble polymer, or a mixture thereof; (d) an enteric coating layer coated on the sustained-release coating layer with an enteric polymer, a water-insoluble polymer, or a mixture thereof.

Korean Patent Laid-Open Publication No. 2007-42073 discloses a drug-containing layer containing a drug on the surface of at least one hydrophobic multi-unit core selected from the group consisting of waxes, higher fatty acids and glyceryl fatty acids, A sustained release multi-unit formulation comprising a control membrane is disclosed.

All of these patents relate to multi-unit formulations, with reference to the introduction of a drug layer on an inert core, but none of the references disclose that when two or more active ingredients are introduced into a multi-unit dosage form with each separate drug layer Problems that may arise, and more specifically, there is nothing to note about the problems that arise when coating a second layer comprising a particular active ingredient on the enteric layer.

The inventors of the present invention have found that, in a pharmaceutical composition suitable for constituting an intraoral buccal formulation as a multi-unit system, the composition of the drug layer adjacent to the enteric layer, more specifically the composition of the second drug layer introduced into the enteric layer surface And that the coating can be smoothly carried out by introducing an alkalizing agent, leading to the present invention.

Korean Patent Publication No. 2012-31002 Korea Patent Publication No. 2011-113940 Korea Patent Publication No. 2007-42073

It is a further object of the present invention to provide a pharmaceutical composition suitable for constituting an oral inhalation formulation as a multi-unit system, wherein the first active ingredient exhibits sustained release and enteric release and the second active ingredient exhibits a fast release, The problem is solved.

In order to solve the above problems, the present invention proposes the following solution means.

A pharmaceutical composition comprising a plurality of unit units comprising two or more active ingredients, wherein the unit unit comprises: an inert core; A first layer coated on the inert core; And a second layer coated on the first layer, wherein the first layer contains a first active ingredient, and the second layer contains a second active ingredient that is the same as or different from the first effective ingredient. ≪ / RTI > is provided.

Since the pharmaceutical composition of the present invention has the same degree of drug release as compared with a single preparation, a pharmacological effect equivalent to that of a single preparation can be expected. It is expected that dosage compliance will be improved because the number of dosage forms taken is reduced. Particularly, according to the present invention, since the second layer coating on the enteric layer is smoothly applied on the enteric layer, the problem of coating the enteric layer on the enteric layer can be solved.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a diagram showing the realization of a composition coated up to the second drug layer of Example 1. Fig.
FIG. 2 is a view showing a state in which the composition coated up to the second drug layer of Example 2 is observed. FIG.
Fig. 3 is a photograph showing a film-coated composition up to the second drug layer of Example 3. Fig.
FIG. 4 is a view showing a real image of a composition coated up to the second drug layer of Example 4. FIG.
5 is a SEM (scanning electron microscope) image of the composition prepared in Example 1. Fig.
FIG. 6 is a photograph showing the inspection of the composition of the second drug layer coating of the comparative example. FIG.
FIG. 7 is a view showing still another inspection of a composition in which a second drug layer coating of Comparative Example is attempted. FIG.
FIG. 8 is another view showing a composition of a second drug layer coating of Comparative Example. FIG.
9 is a view showing still another inspection of a composition in which a second drug layer coating of the comparative example is attempted.
FIG. 10 is a scanning electron microscope (SEM) image of a composition prepared according to a comparative example.

Hereinafter, the present invention will be described in detail.

The present invention relates to a pharmaceutical composition having a multiple unit system in which the first active ingredient achieves release and enteric release and the second active ingredient achieves immediate release.

Specifically, the present invention relates to a pharmaceutical composition comprising a plurality of unit units comprising two or more active ingredients, wherein the unit unit comprises: an inert core; A first drug layer coated on the inert core; And a second drug layer coated on the first drug layer, wherein the first drug layer includes a first effective ingredient, and the second drug layer contains a second effective ingredient that is the same as or different from the first effective ingredient, .

The term "unit unit" in the present invention means a discrete unit including an inert core, a first drug layer and a second drug layer, and the pharmaceutical composition of the present invention includes a plurality of the unit units.

The inert core refers to a pharmaceutically inert core according to the present invention. The inert core includes a water-soluble core such as sugar, a water-insoluble polymer core such as cellulose sphere, a wax And the like, and water-insoluble polymer cores are preferably used, but the present invention is not limited thereto.

The first layer coated on the inert core means a layer containing a first active ingredient, and the first active ingredient contained in the first layer is selected from the group consisting of α-blockers such as alfuzosin, prazosin May be selected from the group consisting of doxazosin, tamsulosin, terazosin, silodosin and pharmaceutically acceptable salts thereof, preferably tamsulosin or a pharmaceutically acceptable salt thereof, Or a pharmaceutically acceptable salt thereof.

Tamsulosin is (R) -5- (2- {[2- (2-ethoxyphenoxy) ethyl] amino} propyl) -2-methoxybenzene-1 -sulfonamide and is represented by the following structural formula.

It is known that tamsulosin or its salt (hereinafter abbreviated as "tamsulosin") has an adrenergic α1A receptor blocking action, in particular its hydrochloride (tamsulosin hydrochloride) has an α1 receptor blocking action in the urethra and prostate, It is commonly used as an agent for improving the urinary disturbance caused by the enlargement of the prostate by lowering the negative pressure of the prostate of the urethra pressure curve. In addition, it is clinically proven that hydrochloric acid tamsulosin is effective for the treatment of lower urinary tract, and it is a clinically very useful drug. Tamsuloghin is marketed as a registered trademark such as a day.

The second active ingredient contained in the second drug layer may be an active ingredient equal to or different from the first active ingredient and is preferably a muscarinic antagonist such as Solifenacin, Darifenacin, Zamifenacin, Tolterodine, Oxybutinin and pharmaceutically acceptable salts thereof, more preferably solifenacin or a pharmaceutically acceptable salt thereof.

Solifenacin is represented by the following structural formula and its chemical name is (R) -quinuclidin-3-yl (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate

Solifenacin or its salt (hereinafter abbreviated as "solifenacin") has an excellent selective antagonistic action against muscarinic M3 receptors and has been shown to be effective in the treatment of neurogenic urinary frequency, neurogenic bladder, enuresis, unstable bladder, bladder relaxation, It has been reported that it is useful as a preventive or therapeutic agent for gastrointestinal diseases such as urinary incontinence and urinary frequency, chronic obstructive pulmonary disease, chronic bronchitis, respiratory diseases such as asthma and rhinitis, irritable bowel syndrome, chronic colitis and diverticulitis.

In particular, the present compound is an M3 receptor antagonist having high selectivity for M3 receptors present in smooth muscle or intestinal tissue compared to the M2 receptor present in the heart and the like and having little adverse effects on the heart etc. Especially, , Chronic bronchitis, asthma and rhinitis, and the like. Solifenacin is marketed as VESIcare (registered trademark) as a treatment for urge urgency, urinary frequency and urge incontinence in overactive bladder.

In addition, several studies have been conducted on the combination of tamsulosin and solifenacin (Efficacy and safety of solifenacin plus tamsulosin in men with voiding and storage lower urinary tract symptoms: results from a phase 2, dose-finding study (SATURN) .2013 Sep; 64 (3): 398-407), but studies on pharmaceutical compositions including tamsulosin and solifenacin are relatively few.

In particular, tamsulosin should be given an enteric property while controlling its release, and solifenacin should be formulated as a high-solubility substance to achieve a desirable in vivo profile, No attempt has been made to.

As a result, there is a need to provide a pharmaceutical composition containing tamsulosin and solipenacin as a method for improving the lower urinary tract symptom associated with enlargement of the prostate, As a mode of administration, there is a demand for a pharmaceutical composition that gives rapid release properties to solifenacin while controlling the release of tamsulosin. Since the drug elution rates of these preparations are different, It is also required to provide an agent with little change in drug releasability.

Particularly, when constructing a composition that can be co-administered using tamsulosin and solifenacin in a multi-unit system, in the case of introducing an enteric layer into a drug layer containing tamsulosin, The problem that the drug layer is not smoothly coated and the means for solving the problem are not known at all.

The first drug layer of the pharmaceutical composition of the present invention may further comprise a controlled release agent for releasing the first active ingredient, more preferably a controlled release agent for releasing the first active ingredient on the first drug layer A control emission layer may further be included.

Controlled emitters that can be used for the controlled release include, but are not limited to, polymethacrylates, polymethylmethacrylates, polyvinyl acetate, polyvinylpyrrolidone, vinyl acetate-polyvinylpyrrolidone copolymers, polyox, Cellulose acetate, guar gum, locust bean gum, acacia gum, gum arabic, gellan gum, and xanthan gum, which are selected from the group consisting of polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, But are not limited thereto and all the pharmaceutical agents which can be used for controlled release of the active ingredient are included in the scope of the present invention.

An enteric layer may further be included on the first drug layer or the controlled release layer of the pharmaceutical composition of the present invention.

The pharmaceutical base used in the enteric layer may be selected from the group consisting of hydroxypropylmethylcellulose phthalate, methacrylic acid copolymer, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropylmethylcellulose acetate succinate, polyvinylacetate phthalate, cellulose acetate trimellitate But are not limited to, all of the pharmaceutical bases which can be used for intestinal absorption in an environment of pH 5.5 or more avoiding gastrointestinal absorption of the drug, include, but are not limited to, And are included in the scope of the present invention.

The second drug layer of the pharmaceutical composition of the present invention may further include an alkalizing agent.

According to an embodiment of the present invention, when a complex agent for achieving combined release of sustained release and rapid release without an alkalizing agent is formed in the second drug layer, the second drug layer is not coated properly on the enteric layer, There is a problem that the degree of classification of the unit is deteriorated and the composition is agglomerated to make a composition which is industrially unavailable. On the other hand, there was no such problem when the second drug layer containing the alkalizing agent was coated on the enteric layer. (See Figs. 1 to 10)

The alkalizing agent that can be included in the second drug layer is preferably selected from the group consisting of sodium phosphate monobasic, sodium phosphate dibasic, mono potassium phosphate, Phosphate, Potassium Phosphate tribasic, Potassium Pyrophosphate, Sodium Pyrophosphate anhydrous, Calcium Phosphate dibasic anhydrous, Calcium Phosphate monobasic, sodium bicarbonate At least one selected from the group consisting of sodium bicarbonate, sodium carbonate anhydrous, magnesium hydroxide, magnesium oxide, magnesium carbonate and meglumine, , More preferably a group consisting of sodium dihydrogenphosphate, disodium hydrogenphosphate, potassium dihydrogenphosphate and magnesium oxide 1 may be at least member selected from.

The pharmaceutical composition of the present invention may be prepared by oral cavity disruption, but is not limited thereto.

Hereinafter, embodiments of the present invention will be described in detail with reference to the drawings. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Example 1.

Step 1. Preparation of new drug coating layer by tamsulosin

20.0 mg of Celerite beads having a size of 50 to 200 탆 was placed in a fluidized bed coater and dispersed in a mixed solution of 2.0 mg of purified water and 18.0 mg of methanol, 0.2 mg of neom hydrochloric acid, 0.2 mg of hydroxypropyl methylcellulose and 0.2 mg of talc, To prepare a drug coating layer.

The coating conditions were spray air of 1.0 to 1.5 bar, inlet air temperature of 45 to 50 ° C and flow of 30.

Step 2. Production of the western layer

The pellet formed with the drug coating layer obtained in Step 1 was coated with a coating solution prepared by dispersing 12.3 mg of Kollicoat SR 30D, 0.18 mg of TEC and 1.48 mg of talc in 15.0 mg of purified water in a fluidized bed coater to prepare a sustained-release coating layer.

Coating conditions were Spray Air 1.5 bar, Inlet Air temperature 35-45 ° C, Flow 30-35.

Step 3. Preparation of an enteric coating layer

The pellet formed with the drug coating layer and the sustained-release layer obtained in Step 2 was coated with a coating solution prepared by dispersing 34.4 mg of Eudragit L30D-55, 9.5 mg of Aquacoat, 1.02 mg of TEC and 2.56 mg of talc in 13.0 mg of purified water in a fluidized bed coater An enteric coating layer was prepared.

The coating conditions were Spray Air 1.5 bar, Inlet Air temperature 30-35 ° C, Flow 30.

Step 4. Preparation of Solifenacin Drug Layer

The pellet obtained in step 3 was coated with a coating solution prepared by dispersing 5.0 mg of solpenacin succinic acid, 0.15 mg of copovidone, 1.24 mg of dihydrogenphosphate and 5.0 mg of talc in 28.2 mg of purified water in a fluidized bed coater to prepare a drug layer.

The coating conditions were Spray Air 2.04 bar, Inlet Air temperature 45-50 ° C, Flow 40.

Step 5. Fabrication of Taste Masking Layer

The pellets obtained in step 4 were coated with a coating solution prepared by dispersing 9.14 mg of Eudragit EPO, 3.66 mg of magnesium stearate, 1.46 mg of stearic acid, 1.13 mg of sodium lauryl sulfate and 5.0 mg of talc in purified water (69.0 mg) masking layer.

The coating conditions were Spray Air 2.04 bar, Inlet Air temperature 35-45 ° C, Flow 40.

Step 6. Preparation of a Multilayer Coating Containing Tablet

The spray-dried mannitol, crospovidone, magnesium stearate and silicon dioxide were mixed in a mixer so that the total weight of the pelletized layer obtained in step 5 was 250 mg, and the mixture was sieved through a 20 mesh sieve to obtain a hardness of 2 to 6 kp Tablets containing 0.2 mg of fresh hydrochloric acid and 5.0 mg of solifenacin succinic acid per tablet were prepared.

Example 2.

The drug layer was prepared by coating the pellet prepared in step 3 of Example 1 with a coating solution prepared by dispersing 5.0 mg of solpenacin succinic acid, 0.15 mg of copovidone, 1.42 mg of disodium hydrogenphosphate, and 5.0 mg of talc in 28.2 mg of purified water .

And a coating solution prepared by dispersing the coating solution in a mixed solution to prepare a multilayer coating layer. The manufacturing steps 5 and 6 were carried out in the same manner as in Example 1.

Example 3.

The pellet prepared in step 3 of Example 1 was coated with a coating solution prepared by dispersing 5.0 mg of solipenacinsuccinic acid, 0.15 mg of copovidone, 1.36 mg of potassium dihydrogenphosphate and 5.0 mg of talc in 28.2 mg of purified water to prepare a drug layer Respectively.

And a coating solution prepared by dispersing the coating solution in a mixed solution to prepare a multilayer coating layer. The manufacturing steps 5 and 6 were carried out in the same manner as in Example 1.

Example 4.

The drug layer was prepared by coating the pellet prepared in step 3 of Example 1 with a coating solution prepared by dispersing 5.0 mg of solpensacin succinic acid, 0.15 mg of copovidone, 0.4 mg of magnesium oxide and 5.0 mg of talc in 28.2 mg of purified water.

And a coating solution prepared by dispersing the coating solution in a mixed solution to prepare a multilayer coating layer. The manufacturing steps 5 and 6 were carried out in the same manner as in Example 1.

Comparative Example

The drug layer was prepared by coating the pellet prepared in step 3 of Example 1 with a coating liquid prepared by dispersing 5.0 mg of soliphenacinsuccinic acid and 0.15 mg of copovidone in 28.2 mg of purified water.

Crospovidone, magnesium stearate, and silicon dioxide were mixed with the granules obtained by coating with the coating solution prepared by dispersing in the mixed solution, and 0.2 mg of purified hydrogensulfuric acid per tablet and 5.0 mg of solifenacin succinic acid were mixed .

Experimental Example 1: SEM image measurement

The particle morphology was observed with a scanning electron microscope (S-3400N / Hitachi, Japan) at an accelerating voltage of 5 KV. Approximately 0.5 mg of the sample was applied on a 5 mm * 5 mm graphite tape, fixed on an aluminum plate, and coated with gold / palladium thin film of 200 A thickness by coating for 40 seconds at a beam current of 38-42 mA .

As a result of SEM image measurement as described above, the pharmaceutical composition prepared according to Example 1 of the present invention showed that the individual particles were uniformly and very smoothly coated, while the pharmaceutical composition prepared according to Comparative Example was coated unevenly and roughly . (See Figures 5 and 10)

Claims (11)

A pharmaceutical composition comprising a plurality of unit units,
Inert core;
A first drug layer coated on the inert core;
And a second drug layer coated on the first drug layer,
Wherein the first drug layer is coated with an enteric layer at the outermost layer, the second drug layer comprises an alkalizing agent,
Wherein the first drug layer comprises a first active ingredient and the second drug layer comprises a second active ingredient that is the same or different from the first active ingredient. The composition according to claim 1, wherein the first active ingredient is selected from the group consisting of alfuzosin, prazosin, doxazosin, tamsulosin, terazosin, silodosin, Acceptable salts and the second active ingredient is selected from the group consisting of Solifenacin, Darifenacin, Zamifenacin, Tolterodine, Oxybutinin, ≪ / RTI > or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof. 3. The pharmaceutical composition according to claim 2, wherein the first active ingredient is tamsulosin or a pharmaceutically acceptable salt thereof and the second active ingredient is solifenacin or a pharmaceutically acceptable salt thereof. 2. The pharmaceutical composition according to claim 1, further comprising a control release layer on the first drug layer for releasing the first active ingredient. 5. The method of claim 4, wherein the controlled release agent used in the controlled release layer is selected from the group consisting of polymethacrylate, polymethyl methacrylate, polyvinylacetate, polyvinylpyrrolidone, vinyl acetate-polyvinylpyrrolidone copolymer, poly A group consisting of lactose, glyceryl behenate, glyceryl behenate, solid fat, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, cellulose acetate, guar gum, locust bean gum, acacia gum, gum arabic, , Wherein the pharmaceutical composition is at least one selected from the group consisting of: delete The pharmaceutical composition according to claim 1, wherein the pharmaceutical base used in the enteric layer is selected from the group consisting of hydroxypropylmethylcellulose phthalate, methacrylic acid copolymer, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropylmethylcellulose acetate succinate, polyvinyl acetate Phthalate, cellulose acetate trimellitate, carboxymethylcellulose, and shellac. ≪ RTI ID = 0.0 > 8. < / RTI > delete The method of claim 1, wherein the alkalizing agent is selected from the group consisting of sodium phosphate monobasic, sodium phosphate dibasic, mono potassium phosphate, dipotassium phosphate, tribasic potassium phosphate (Potassium Phosphate tribasic), Potassium Pyrophosphate, Sodium Pyrophosphate anhydrous, Calcium Phosphate dibasic anhydrous, Calcium Phosphate monobasic, Sodium Bicarbonate, Sodium Carbonate Wherein the pharmaceutical composition is at least one selected from the group consisting of sodium carbonate anhydrous, magnesium hydroxide, magnesium oxide, magnesium carbonate and meglumine. . The pharmaceutical composition according to claim 1, wherein the alkalizing agent is at least one selected from the group consisting of sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, and magnesium oxide. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is an oral cavity disintegration tablet, a tablet tablet, a foamable tablet, a tablet, a dispersion tablet, a tablet, a dissolution tablet or a chewable tablet.

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