KR20120028720A - Sustained release pellets containing duloxetin - Google Patents

Abstract

PURPOSE: A pharmaceutical formulation containing duroxetin and pharmaceutically acceptable salt thereof is provided to ensure safety and enteric property. CONSTITUTION: A sustained release pharmaceutical formulation comprises: a core coated with duloxetin or pharmaceutically acceptable salt thereof or a core in which duroxetin or pharmaceutically acceptable salt thereof is mixed; a water soluble separate layer surrounding the core; and an enteric layer containing carboxy methyl ethyl cellulose. The pharmaceutical formulation is pellet and contains duroxetin hydrochloride.

Description

Sustained Release Pellets Containing Duloxetin

The present invention relates to a delayed-release enteric preparation comprising duloxetine or a pharmaceutically acceptable salt thereof.

The chemical name of duloxetin is (+)-(S) -N-methyl-3- (naphthalen-1-yloxy) -3- (thiophen-2-yl) propan-1-amine, currently hydrochloride The form is being used to treat depression. The molecular formula of duloxetine hydrochloride is C ₁₈ H ₁₉ NOS-HCl, and has a molecular weight of 333.88 g / mol. Duloxetine hydrochloride is a selective serotonin-norepinephrine reuptake inhibitor (SNRI) and has antidepressant effects because of this effect.

Duloxetine hydrochloride is made from enteric coated pellets and is marketed by Eli Lilly in capsule form and is known to contain hydroxypropylmethylcellulose acetate succinate (HPMCAS) which is dissolved at pH 5 or higher as an enteric film forming material. .

Specifically, U.S. Patent No. 5,508,276 discloses a delayed release formulation in the form of an enteric duloxetine pellet. The disclosed enteric coating film layer used HPMCAS among enteric polymers which are not dissolved in gastric acid but dissolved at pH 5 or higher. However, US Pat. No. 5,508,276 discloses that when HPMCAS is used in suspension form, the suspension must not only be cooled down to 20 ° C. or lower before use, but also the cooling dryer's pipes and nozzles can be cooled when a small diameter pipe is used for coating. There are many disadvantages in the preparation of duloxetine delayed-release pellets using HPMCAS.

On the other hand, U.S. Patent No. 5,508,276 describes that when HPMCAS is used in the form of an aqueous solution, it must be neutralized with ammonia to promote dissolution of HPMCAS. U. S. Patent No. 5,508, 276 also describes that duloxetine reacts with the enteric coating agent to form a coating that does not slowly dissolve or dissolve, which may result in poor release behavior and low bioavailability of duloxetine.

Delayed release formulations prevent the active pharmaceutical ingredient from being exposed in an acidic environment while preventing the acid sensitive active pharmaceutical ingredient from degrading or irritating the stomach of the patient. The preparation of duloxetine hydrochloride is appropriate for such delayed release formulations, but the above problems of duloxetine formulations according to the enteric base should be solved.

Therefore, the technical problem to be achieved by the present invention is to provide an easy preparation, no problem according to the manufacturing process, and excellent stability of duloxetine or a pharmaceutically acceptable salt-containing delayed-release enteric preparation thereof.

In order to achieve the above technical problem, the present invention is a core coated with duloxetin (duloxetin) or a pharmaceutically acceptable salt thereof or a core mixed with duloxetin (duloxetin) or a pharmaceutically acceptable salt thereof; A water soluble separation layer surrounding the core; And duloxetine or a pharmaceutically acceptable salt-containing pharmaceutical formulation thereof (preferably pellets) comprising an enteric layer comprising carboxymethylcellulose surrounding the water soluble separation layer.

The present invention is easy to manufacture when carboxymethylethylcellulose is used as an enteric base in the preparation of duloxetine, and does not cause any problems in the manufacturing process, and in particular, it is more effective in securing the stability of duloxetine. Based.

Preferably, the active ingredient in the pharmaceutical formulation of the present invention is duloxetine hydrochloride.

In this specification, unless stated otherwise, percentages, ratios, proportional ratios, etc., are all based on weight. When referring to the proportion of enteric products, it refers to the proportion of the product in dry form, from which solvents such as water in which the components are dissolved or dispersed are removed.

That is, the present invention relates to a drug layer comprising (a) an inert core, (b) duloxetine or a pharmaceutically acceptable salt thereof (preferably duloxetine hydrochloride) and a pharmaceutically acceptable excipient, (c) separation A pellet comprising a layer and (d) an enteric layer comprising carboxymethylcellulose, or (a) a core comprising duloxetine hydrochloride and a pharmaceutically acceptable excipient, (b) a separation layer and (c) carboxymethyl Provided is a pellet comprising an enteric layer comprising ethylcellulose.

The core is a core that does not formally interact with duloxetine hydrochloride, and any inert material or mixture of materials known to those skilled in the art can be used. Preferably, sugar fine particles, microcrystalline cellulose fine particles, and the like may be used as the core.

Typically the size of the core depends on the size of the pellet to be produced. In general, the pellets according to the present invention may be about 0.1-1 mm in diameter and the diameter size of the core may be about 0.3-0.8 mm to provide pellets of desired size about 0.5-1 mm in diameter. In order to improve the homogeneity of the various, two or three or more coatings used, the completeness of the coating surface, and the content uniformity of the intended target, it is preferable to use those in which the particle distribution range of the core is suitably narrow.

When preparing pellet formulations according to the invention using an inert core that does not contain duloxetine, the duloxetine is generally coated on the inert core such that the final concentration of the drug is about 1-15% by weight of the product. Of course, the amount of duloxetine may vary depending on the dosage required and the amount of pellets required to administer. The dosage of duloxetine is about 1-50 mg, more typically 5-20 mg, and the usual dosage of pellets is that which can be filled in a commercially available gelatin capsule. Thus, comparing the amount of gelatine capsules filled with the desired dosage, the concentration range of duloxetine hydrochloride in the product is about 1-15% by weight.

The drug layer coated on the inert core may comprise one or more pharmaceutically acceptable excipients. As such excipients, fillers, binders, glidants, coatings and antistatic agents are preferably used, and most preferably selected from white sugar, lactose, povidone, colloidal silicon dioxide, hypromellose and talc.

The drug layer is preferably present in an amount of about 40-90% by weight of the formulation, more preferably in an amount of about 40-75% by weight of the formulation.

A simple process of coating using a non pareil seed (NPS) as the core and enclosing it with a duloxetine-containing drug layer is as follows. First, the white glycoside granules are put into a manufacturing apparatus such as a centrifugal granulator / coater (CF coater), and the surface of the glycoside granules is sprayed with an adhesive liquid or a binder to be wetted. It is a "powder coating" process which adds the component which forms a drug layer, such as a powder, and dries this mixture. Alternatively, another convenient process of coating the core glycoside granules with a layer of duloxetine drug is the addition of duloxetine, a binder and a pharmaceutically acceptable additive while centrifugal rotation of the glycoside granules in a manufacturing apparatus such as a centrifugal coating granulator. A method for producing spherical particles using dry air using hot air drying while spraying the dissolved / dissolved binding solution on the white ball sphere granules, but this method has a low air flow rate and low drying ability, so that the coating rate This is limited, and there is a disadvantage that the manufacturing process is inevitably long for preventing adhesion and aggregation between particles and perfection of properties. Another process to improve this is to prepare spherical granules (pellets) containing pharmaceutically active ingredients in a fluidized bed coating device (using Urster method or rotary coating method). Containing spherical granules (pellets) can be prepared to continuously form a protective coating and enteric coating. To this end, the coating solution is sprayed from the bottom and spherical particles flow through the column to form a continuous coating, and the bottom is a rotating plate, and the continuous coating liquid is sprayed next to it. It includes a side coating method. In this coating method using a fluidized bed, agglomerates of particles to be coated are continuously moved by an air layer flowing in a cylinder.

A separation layer between the duloxetine containing core (or core and drug layer) and the enteric layer may be located, which is not necessary but is preferred for the stability of the formulation of the invention. The separation layer may help to improve the stability of duloxetine by blocking the contact of duloxetine with the components in the enteric layer and may further protect duloxetine from photoexposure. In addition, such a separation layer can smooth the surface of the core or drug layer so that the enteric layer can be densely coated, thereby further ensuring the delayed release property, which is another object of the present invention.

Pharmaceutically acceptable sugars, water-soluble polymers, and the like may be used as the material forming the separation layer, and a binder, an excipient, a surfactant, a lubricant, an anti-sticking agent, and the like may be further used. For example, hypromellose, povidone, hydroxypropylcellulose and similar materials can be used to increase the adhesion and adhesion of the separation layer. Moreover, it is desirable to use filling excipients in the separation layer to increase the smoothness and firmness of the separation layer. For this purpose, the coating agent may be selected from OPDRAY ™, EASPRAY ™ or commercially mixed coating materials and hypromellose. Such additional pharmaceutically acceptable excipients may include excipients commonly used in pharmaceutical formulations that do not negatively interact with duloxetine hydrochloride.

The separation layer is preferably present in an amount of about 8-60% by weight of the formulation. More preferably, the separation layer is present at about 0.5-10% by weight of the formulation. The separation layer is preferably present in a weight ratio of about 0.5: 1 to about 10: 1 relative to the enteric layer.

The duloxetine or pharmaceutically acceptable salt-containing pellets of the present invention also include an enteric layer that does not dissolve at the pH of the stomach but dissolves at the pH of the intestine, ie, a delayed release layer that prevents the release of the stomach. Carboxymethylethyl cellulose for the purpose of. Preferably, such carboxymethyl cellulose has a carboxyl methyl group (-CH ₂ COOH: 59.04) is about 8.9-14.9% of the total weight of the polymer, the ethoxyl group (-OC ₂ H ₅ : 45.06) is about 32.5-43 %to be. Compared to other enteric polymers, the carboxymethyl cellulose is more effective in securing the stability of duloxetine, and the coagulation and moisture resistance of the polymer itself is less, so that the storage and coating process is easy, and the enteric stability is stable even in long-term harsh conditions. Is maintained. In addition, the carboxymethylethyl cellulose applied to the duloxetine-containing pellet according to the present invention can be easily used in the coating process in the form of a solution or an aqueous suspension using an aqueous solvent or an organic solvent such as purified water.

More specifically, there is no phthalic acid group, such as hydroxypropylmethylcellulose phthalate, which is a commonly used enteric polymer, and thus has excellent safety for the human body. In the case of succinic acid hydroxypropyl cellulose acetate, which is a highly enteric base having high moisture resistance, it should be stored in a dry condition in order to suppress hydrolysis of acetic acid and succinic acid. In order to improve this problem, when applying HPMCAS in the form of a suspension, not only the suspension must be cooled to 20 ° C. or lower, but also a small diameter pipe is used, and a pipe and a nozzle of the spray dryer have a disadvantage. When HPMCAS is applied in the form of an aqueous solution, there is a disadvantage in that HPMCAS must be neutralized with, for example, ammonia to promote its dissolution.

The present invention provides duloxetine or a pharmaceutically acceptable salt-containing pharmaceutical preparation thereof, preferably duloxetine hydrochloride-containing multilayer pellets, which is easy to manufacture, ensures stability of duloxetine, and is excellent in enteric (delayed release) properties. .

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

Example 1 Preparation of 10 mg of Duroxetine-containing Formulation

A duloxetine hydrochloride-containing formulation containing 10 mg was prepared as duloxetine as shown in Table 1 below.

division ingredient Weight ratio 1. Core part White billiard granules 32.23% 2. Drug layer Duloxetine Hydrochloride 7.24% Lactose 32.08% Crospovidone 5.15% Hydroxypropylcellulose 0.26% 3. Separation layer Hypromellose 2910 1.74% Polyethylene Glycol 6000 0.17% Starch 0.19% Light anhydrous silicic acid 0.58% Talc 0.10% 4. Enteric layer Carboxymethyl Ethyl Cellulose 15.48% Glyceryl Fatty Acid Ester 1.55% Starch 1.29% Light anhydrous silicic acid 1.29% Talc 0.65%
100.00%

Purified water was added to the binder preparation tank, and lactose, crospovidone, hydroxypropyl cellulose, and duloxetine hydrochloride were added thereto, followed by homogeneous stirring, dissolution and dispersion of the solids content in the purified water to 7-15%. The coating solution of the drug layer was prepared by passing through a sieve No. 80. White glycoside granules (average particle size 500-600 μm) were introduced into a container of a fluidized bed coater using a Wurster apparatus and flowed. Thereafter, the drug layer coating solution was mixed and sprayed onto the granular granules flowing in the fluidized bed coater. The drug layer coating solution was sprayed at a spray air pressure of 3.0 bar through a 1.2 mm nozzle, and the intake temperature was 60 ± 5 ° C and the exhaust temperature was 45 ± 5 ° C. The drug layer-containing core containing duloxetine hydrochloride was adjusted while adjusting the flow of air. Was prepared.

Subsequently, hypromellose 2910, polyethylene glycol 6000, starch, hard silicic anhydride, and talc are dissolved or dispersed in purified water to prepare a separation layer coating solution, so that hypromellose 2910 is about 5-10% with respect to purified water. Used. The separation layer coating solution was sprayed onto the drug layer-containing core injected into the fluidized bed coating machine using the Wurster apparatus at a spray air pressure of 2.5 bar through a 1.2 mm nozzle, at which the intake temperature was 60 ± 5 ° C and the exhaust temperature was 45 ± 5 ° C. Spherical granules coated to the separation layer were prepared while adjusting the amount of air flowing and the amount of coating.

In order to form an enteric coating layer, enteric coating solution is dissolved by dispersing or dispersing carboxymethyl cellulose, glyceryl fatty acid ester, starch, hard silicic anhydride and talc in purified water so that the carboxymethyl cellulose is about 8-12% of purified water. Was prepared. The separator-coated spherical granules were continuously sprayed in a fluidized bed coater while spraying the enteric coating solution under the same conditions as the separation layer coating to prepare an enteric pellet as a final product. No problem was found in the manufacturing process, and when observed under a microscope, it was confirmed that a uniform enteric layer was formed.

Example 2 Preparation of 20 mg of Duroxetine-containing Formulation

A duloxetine hydrochloride-containing formulation containing 20 mg of duloxetine was prepared as shown in Table 2 below. The preparation method was the same as in Example 1.

division ingredient Weight ratio 1. Core part White billiard granules 32.23% 2. Drug layer Duloxetine Hydrochloride 14.48% Lactose 24.84% Crospovidone 5.15% Hydroxypropylcellulose 0.26% 3. Separation layer Hypromellose 2910 1.74% Polyethylene Glycol 6000 0.17% Starch 0.19% Light anhydrous silicic acid 0.58% Talc 0.10% 4. Enteric layer Carboxymethyl Ethyl Cellulose 15.48% Glyceryl Fatty Acid Ester 1.55% Starch 1.29% Light anhydrous silicic acid 1.29% Talc 0.65% 100.00%

No problem was found in the manufacturing process, and when observed under a microscope, it was confirmed that a uniform enteric layer was formed.

Example 3 Appearance and Content Stability Evaluation

The duloxetine hydrochloride-containing pellets prepared in Example 2 were packaged in a PP bottle, which is a virtue packaging container, for six months under conditions of short-term accelerated stability test at 40 ± 5 ° C. and a relative humidity of 75%. And the stability of the formulation through the dissolution test was evaluated.

standard initial 1 month 2 months 4 months 6 months Statue White spherical pellets fitness No change No change No change No change content(%) 95-105 101.3 99.2 99.7 100.8 98.1 Dissolution rate
(%) 1 liquid ≤5%, 60 minutes - - - - - 2 drops ≥70%, 45 minutes 88.7 90.1 92.6 86.9 90.6

As shown in Table 3 above, the duloxetine formulations according to the present invention showed good stability.

Claims (4)

Cores coated with duloxetin or a pharmaceutically acceptable salt thereof or mixed with duloxetin or a pharmaceutically acceptable salt thereof; A water soluble separation layer surrounding the core; And an enteric layer comprising carboxymethyl cellulose surrounding the water soluble separation layer, duroxetine or a pharmaceutically acceptable salt-containing pharmaceutical formulation thereof. The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation is a pellet formulation. The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation comprises duloxetine hydrochloride. Sugar cores; A drug layer containing duloxetine hydrochloride, lactose and crospovidone surrounding the core; A separation layer comprising hydroxypropylmethylcellulose surrounding the drug layer; And an enteric layer comprising carboxymethylethyl cellulose surrounding the separation layer.