TWI408130B - Duloxetine enteric coated pharmaceutical composition - Google Patents

Abstract

A duloxetine enteric-coated pharmaceutical composition includes a core, a drug-loaded layer encapsulating the core, an intermediate controlled-release layer encapsulating the drug-loaded layer, and an enteric-coated controlled-release layer. The drug-loaded layer contains duloxetine or a pharmaceutically acceptable salt thereof and a hydrophilic polymer. The intermediate controlled release layer contains ethyl cellulose (EC). The enteric-coated controlled-release layer contains hydroxypropyl methylcellulose phthalate (HPMCP). The present invention discloses a well protected duloxetine enteric-coated pellet comprising an intermediate controlled-release layer.

Description

Roxetine casing composition

The present invention relates to a casing pharmaceutical composition, and more particularly to a pharmaceutical composition having a casing controlled release layer and an intermediate controlled release layer.

Duloxetine is currently used clinically as a depressant. Deroxetine is (+)-N-methyl-3-1(1-naphthyloxy)-2-thiophene propylamine and is widely used as its bismuth ruthenate. The antidepressant effect of duroxetine may be related to the serotonin activity (Serotonergic) of the central nervous system and the noradrenergic activity. Preclinical tests show that dextroxetine can effectively block the resorption of serotonin and norepinephrine. And only slightly inhibited the reabsorption of dopamine.

Early dosage forms and clinical developments have shown that it is a suitable practice to formulate a casing pharmaceutical composition due to the unstable nature of the rosinine in an acidic solution. The preparation of the oral enteric pharmaceutical composition enables the product to be in an acidic environment in the stomach of the patient without change. When leaving the stomach and entering the intestinal tract below the duodenum, it rapidly dissolves and releases the active ingredient due to an increase in pH. Oral enteric coating pharmaceutical compositions, usually in the form of a lozenge or pill, wherein the active ingredient is internal to the lozenge or pill.

It has now been discovered that the dextroxetine reacts with a number of casing coatings to form a slow or insoluble coating, and thus the expected cross-reactivity occurs, resulting in poor release efficiency and low bioavailability of the formulation in pellet form. . In summary, it is currently desired to develop a pharmaceutical composition having a protective effect on a drug and having a casing coating.

In order to solve the above problems, the Republic of China Patent No. 111828 discloses a casing of ruthine. a formulation that utilizes a separation layer to provide a smooth substrate for coating the casing layer, thereby extending the resistance of the pellet to acidic conditions and inhibiting the interaction between the agent and the casing polymer in the casing layer to improve stability. Protects the agent from exposure to light and improves its stability. However, if the separation layer does not have an intermediate controlled release or good drug protection effect, the protective effect on the drug during the preparation process is inconspicuous, and the reaction will be caused by contact with the casing material. In the human body, the casing layer dissolves when entering the intestines, which will cause the drug layer to immediately contact the environment, and may still be in contact with the digestive acid or acid digested digestive material in the duodenum, because the previous case also refers to the general ball type. In the preparation of the drug layer, the surface of the sphere may occasionally produce protrusions or small dots caused by irregularities, thereby affecting the smoothness of the separation layer and the drug protection effect, and at the same time affecting the coating effect of the casing layer, indirectly Causes instability of the coating effect of the sucrose capsule.

In summary, it is currently the goal of the process to add the strength of the casing coating and drug protection effect of the oxime shelling pharmaceutical composition and the pharmacy design of the human body performance.

SUMMARY OF THE INVENTION The object of the present invention is to provide a once-sweeting enteric-coated pharmaceutical composition which has an enteric coating effect by an enteric release layer and an intermediate controlled release layer, and achieves protection and controlled release. Among them, the intermediate controlled release layer can provide a smooth matrix, which does not vary according to the shape of the drug layer, and can achieve controlled release of the drug.

According to an embodiment of the present invention, a pharmaceutical composition for a spirulina casing comprises: a core, a drug-loading layer covering the core, an intermediate controlled release layer covering the drug-loading layer, and an intermediate controlled release coating. A casing controlled release layer of the layer. Characterized in that the drug-loading layer comprises a sucrose or a pharmaceutically acceptable salt thereof, and at least one hydrophilic polymer; the intermediate controlled release layer comprises ethyl cellulose and a saccharide or a derivative thereof, wherein the ethyl group Cellulose accounts for the weight percent of the intermediate controlled release layer 15.0%~58%; the casing controlled release layer comprises hydroxypropyl methylcellulose phthalate "Hydroxypropyl methylcellulose phthalate" (HPMCP).

1 , the pharmaceutical composition of the present invention comprises: a core 1, a drug-loading layer 2 covering the core 1, an intermediate controlled-release layer 3 coated with the drug-carrying layer 2, and The casing controlled release layer 4 coated on the intermediate controlled release layer 3. The pharmacy will be described below for each layer.

Core 1: The core comprises round pellets prepared using excipients that are not pharmaceutically active, wherein the excipient species may be lactose, starch (Starch), mannitol (Mannitol), sodium carboxymethylcellulose sodium (Carboxymethylcellulose sodium). (CMC-sodium), Diglycol starch sodium, Sodium chloride, Potassium chloride, Pigment, Alginates, Talc (Talc) ), titanium dioxide, stearic acid, stearate salt, microcrystalline cellulose, glycerol, polyethylene glycol (Glycol), Triethyl citrate (TEC), Tributyl citrate, n-Propyl acetate, Calcium hydrogen phosphate, Sodium phosphite Calcium sulfate, cyclodextrin or castor oil.

At the same time, the core can also be purchased directly from the supplier. The core types that are generally commercially available include (1) sucrose core round particles, (2) core round particles of sucrose and starch, and (3) core of microcrystalline cellulose. Round grain.

Drug-loading layer 2: The drug-loading layer contains an active substance and at least one hydrophilic polymer, and if necessary, a binder, a plasticizer, an anti-adhesive agent or other excipients may be added.

The active substance of the present invention is (6)-N-methyl-3-1(1-naphthyloxy)-2-thienylamine, and is widely used as its ruthenium ruthenate, but is not limited thereto.

Hydrophilic polymers include alkoxypropylmethylcellulose, alkoxypropylcellulose, and polyvidone or other medically acceptable excipients. Among them, the binder may be polyethylene tetrahydropyrrolidone "Polyvinylpyrrolidone" (PVP), gelatin, hydroxyethyl cellulose "Hydroxyethyl cellulose" (HEC), hydroxypropyl fibrin "Hydroxypropyl cellulose" (HPC), hydroxypropyl Methyl cellulose "Hydroxypropylmethylcellulose" (HPMC), vinyl acetate "Vinyl acetate" (VA), polyvinyl alcohol "Polyvinyl alcohol" (PVA), methyl cellulose "Methylcellulose" (MC), ethyl cellulose Ethylcellulose" (EC), hydroxypropyl methyl phthalate "Hydroxypropyl methylcellulose phthalate" (HPMCP), Xanthan gum, alginic acid, alginate, methacrylic acid methacrylate copolymer Highly crystallized processed products (such as Eudragit series, trade name), copolymerized methacrylic acid/methyl methacrylate or polyethylene phthalate (Polyvinyl acetate phthalate) (PVAP).

Among them, the plasticizer comprises glycerin, polyethylene glycol, triethyl citrate (TEC), tributyl citrate, propyl triacetate, diethyl phthalate (DEP) and adjacent Dibutyl phthalate (DBP).

Among them, the anti-adhesive agent contains talc, stearic acid, stearate, sodium stearyl fumarate and Glyceryl behenate, high Kaolin, Colloidal Silicon Dioxide.

Other excipients include lactose, starch, mannitol, sodium carboxymethylcellulose, sodium glycolate glycol, sodium chloride, potassium chloride, pigments, alginates, titanium dioxide, stearic acid, stearates, Microcrystalline cellulose, glycerol, polyethylene glycol, triethyl citrate; tributyl citrate, propyl triacetate, calcium hydrogen phosphate, trisodium phosphate, calcium sulfate, cyclodextrin starch and castor oil.

The intermediate controlled release layer 3: an intermediate controlled release layer having a protective and sustained release effect is coated on the outer side of the drug-loading layer, and the intermediate controlled release layer contains ethyl cellulose. Ethyl cellulose itself has good thermal stability and can maintain softness at low temperatures, so it can quickly form a film coat at a temperature around 30 ° C and keep it smooth, which does not affect its smoothness due to the shape of the original drug layer. Traits, and no changes due to acid or alkaline environment. Therefore, the protective ability of the drug layer is improved and the intermediate controlled release layer matrix is simultaneously used to achieve controlled release of the drug.

Ethyl cellulose is distinguished by a viscosity of 4 to 100 cps, such as EC 4 cps, EC 7 cps, EC 10 cps, EC 14 cps, EC 22 cps, EC 50 cps, and EC 100 cps. Among them, EC 10 cps accounts for 5.0%-70% of the weight of the intermediate controlled release layer, preferably 18%~58%.

In addition, the intermediate controlled release layer may contain other compounds which are available for extended release purposes. For example, other compounds which are capable of delaying release may comprise a methylcellulose processing product (Methocel), an ethyl cellulose aqueous dispersion (Surelease) or an acrylic resin (Eudragit) L30D.

The intermediate controlled release layer may further comprise a hydrophilic substance. The hydrophilic substance includes a sugar and Its derivatives. Examples of the saccharide include monosaccharides, disaccharides, polysaccharides, cellulose or derivatives thereof such as glucose, rhamnose, sucrose, oligosaccharides, galactose, lactose, mannitol, glucose alcohol, dextrin, malt paste Fine, cellulose, sodium carboxymethyl cellulose, or starch.

Among them, the hydrophilic substance can be used as a channel for the water molecules to enter and exit after the casing is dissolved, and release the hydrophilic polymer of the active ingredient adjusting substance and the drug-loading layer, and has the effect of isolating the drug-loading layer and the casing layer. And the effect of controlled release is achieved by the permeability of the hydrophilic substance to achieve the control rate of the release rate of ruthine.

In summary, the intermediate controlled release layer of the present invention has the advantages of good stable drug release and protection of the drug.

Casing Controlled Release Layer 4: Since leucoxetine is a drug with unstable properties in an acidic solution, the effect of the controlled release layer of the casing protects the sedative from passing through the stomach and does not come into contact with the acidic environment; When the stomach enters the small intestine, it can quickly dissolve and release the active ingredient when it is converted to an alkaline environment due to an increase in pH.

The controlled release layer of the casing contains at least hydroxypropylmethylcellulose phthalic acid (HPMCP), which is prepared by reacting phthalic anhydride with HPMC, and is an enteric film which is dissolved by an organic solvent system, and is generally referred to as HP. Mainly the ionization of -COOH in phthalic acid to achieve pH dependence. The Pharmacopoeia (NF XVI, JP XI) has two HPMCP (HP) specifications including HP-50, HP-55 and HP-55S, of which HP-50 can be dissolved in an environment with a pH above 5.0 (≧4.8). HP-55 and HP-55S are soluble in an environment with a pH above 5.5 (≧5.2). The HPMCP used in the present invention accounts for 40% to 90% by weight of the casing controlled release layer, and the HPMCP is selected to include HPMCP 50, HPMCP 55 or HPMCP. 55S.

The enteric release layer may further comprise at least one pharmaceutically acceptable plasticizer such as diethyl phthalate (DEP) or triethyl citrate (TEC).

The objects, technical contents, features and effects achieved by the present invention will be more readily understood from the following detailed description of the embodiments.

Specific embodiment 1 Core layer

Spherical particle

Drug carrier

Main component (relative to the percentage of drug-loaded layer)

Intermediate controlled release layer

Excipients (% of intermediate controlled release layers)

Casing controlled release layer

Excipients (each accounting for the percentage of controlled release layer of the casing)

Specific embodiment 2 Drug carrier

Spherical particle

Main component (relative to the percentage of drug-loaded layer)

Intermediate controlled release layer

Excipients (% of intermediate controlled release layers)

Casing controlled release layer

Excipients (each accounting for the percentage of controlled release layer of the casing)

The manner of preparation of the above examples is disclosed below.

Preparation of drug-loading layer: Hydroxypropyl methylcellulose and polydiethanol were dissolved in water, and the sucrose and talc powder were added, and uniformly stirred and dispersed in the solution. The resulting homogeneous suspension is then spray coated onto the spheres in the Glatt gyro flow bed pelletizer.

The present invention is experimentally produced using the GPCG-1 machine of the German brand Glatt, but the implementation is not limited to the production machine. When the drug-loaded layer is prepared, the amount of the spray liquid needs to be appropriately adjusted according to the conditions of the air volume, the inlet air temperature and the rotational speed. If the amount of the spray liquid is too low, some of the drug solvent will rapidly evaporate, resulting in loss of product content, and the amount of spray liquid is too The assembly caused the solvent to not fully evaporate in time, causing the pellets to adhere to each other, forming a non-holospheric spherical mass called a twin sphere or a triple sphere, which is the most common problem in the process of spraying pellets. Initially use a lower amount of spray liquid, and the coating process proceeds smoothly until the sphere is enlarged, and then the amount of spray liquid is increased.

The inlet air temperature ranges from 28 ° C to about 38 ° C, preferably from 30 ° C to about 38 ° C; the outlet temperature is from 28 ° C to about 36 ° C; the spray volume is from 6 to 12 ml per minute; It is handled satisfactorily under suitable conditions such as 180-360 rpm.

Preparation of intermediate controlled release layer: Hydroxypropyl methylcellulose and sucrose were dissolved in a solution of alcohol and water in a ratio of about 4:1, and ethyl cellulose and talc were slowly added. The spheres placed in the sprayed drug-loaded layer were then placed in a Glatt whirl fluid bed pelletizer and an intermediate controlled release layer was sprayed. The inlet temperature ranges from 28 ° C to about 38 ° C, the outlet temperature is from 26 ° C to about 32 ° C, the spray rate is 4-10 ml per minute, and the rotational speed of the rotating disk is about 180-360 rpm, etc., under good conditions.

Preparation of the controlled release layer of the casing: Dissolving hydroxypropylmethylcellulose phthalic acid (HPMCP) in a mixed solution of alcohol and water in a ratio of about 4:1, and then adding diethyl phthalate and talc to The Glatt Swirling Fluidized Bed Granulator coats the casing layer on the coated intermediate controlled release layer. The inlet temperature ranges from 28 ° C to about 38 ° C; the outlet temperature is from 26 ° C to about 32 ° C; the spray volume is 4-10 ml per minute; the spray pressure is 2.5 bar; the rotating disc speed is about 180-360 rpm and other suitable conditions are good. Operation. Adhesion is prevented by proper temperature and air flow. After the spraying is completed, the drying process is carried out at 42-45 ° C. Finally, the finished pellet was filled into a gelatin capsule as a finished product for the dissolution test.

Referring to Figure 2, a comparison of the experimental results of the present invention with a commercially available original developer of a similar dosage form of the drug is disclosed. The method was as follows: the drug to be tested was placed in a 0.1 N HCl solution for 0.5 hour, and then transferred to a pH 6.8 solution, and the dissolution concentration was measured after the dissolution test. The results show that within 0 to 30 minutes, the casing formulation of the agent of the present invention is designed to have a good controlled release effect compared with the commercially available drug when it is in an acidic environment, and can maintain lower dissolution and avoid the influence of acidic environment. . In the dissolution rate after 30 minutes, it can be seen that the drug is in a higher pH environment and the casing layer is fully dissolved. It can be understood from the comparison that the intermediate controlled release layer effect of the embodiment of the present invention has a protective effect 30 minutes ago, and is delayed in Released in an acidic environment, but does not cause the drug to delay the release of the drug's intestinal tract and miss the drug absorption. Generally, the f2 value is 50% or more with in vitro similarity, especially the specific example 2. It is apparent that there should be an in vitro similarity relationship, and the f2 value is about 64.77%.

In combination with the above description, the pharmaceutical composition of the present invention has an enteric coating effect and an intermediate controlled release layer to have a casing effect and achieve protection and controlled release. Among them, the intermediate controlled release layer can provide a smooth matrix, which does not differ depending on the shape of the drug layer, and can achieve the release of the controlled release drug.

1‧‧‧ core

2‧‧‧ drug carrier

3‧‧‧Intermediate controlled release layer

4‧‧‧Enteric release layer

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a cross-sectional view showing a pharmaceutical composition of a sucrose capsule according to an embodiment of the present invention.

Figure 2 is a graph comparing the dissolution curves of the examples with commercially available samples.

1‧‧‧ core

2‧‧‧ drug carrier

3‧‧‧Intermediate controlled release layer

4‧‧‧Enteric release layer

Claims (9)

A duloxetine casing pharmaceutical composition comprising: a core; a drug-loading layer covering the core, wherein the drug-loading layer comprises: dextroxetine or a pharmaceutically acceptable salt thereof; At least one hydrophilic polymer; an intermediate controlled release layer covering the drug carrier layer, wherein the intermediate controlled release layer comprises: ethyl cellulose (EC), wherein the ethyl cellulose accounts for the weight percent of the intermediate controlled release layer 15.0%-58%; and sucrose, wherein the sucrose comprises 27.19%-38.06% by weight of the intermediate controlled release layer; and a casing controlled release layer covering the intermediate controlled release layer, wherein the casing controlled release layer comprises Hydroxypropyl methylcellulose phthalic acid (HPMCP). The pharmaceutical composition according to claim 1, wherein the hydrophilic polymer comprises a hydrocarbylmethylcellulose, a hydrocarbyl cellulose, a polyvidone or other medically acceptable composition. The excipient. For example, the pharmaceutical composition of claim 1, wherein the ethyl cellulose has a viscosity of 4 to 100 cps. The pharmaceutical composition according to claim 1, wherein the ethylcellulose comprises EC 4 cps, EC 7 cps, EC 10 cps, EC 14 cps, EC 24 cps, EC 50 cps or EC 100 Cps. The pharmaceutical composition of claim 1, wherein the controlled release layer further comprises a pharmaceutically acceptable plasticizer comprising diethyl phthalate (DEP) or lemon. Triethyl acid (TEC). A pharmaceutical composition according to claim 1, wherein the hydroxypropylmethylcellulose phthalic acid (HPMCP) comprises HPMCP 50, HPMCP 55, or HPMCP 55S. For example, in the pharmaceutical composition of claim 1, the hydroxypropylmethylcellulose phthalic acid (HPMCP) accounts for 40% to 90% by weight of the controlled release layer of the casing. A capsule comprising the Rustinidine enteric pharmaceutical composition according to any one of claims 1 to 7. A method for preparing a pharmaceutical composition for preparing a pharmaceutical composition according to any one of claims 1 to 8, which comprises: (a) applying a solution of the drug-loading layer to the core (b) applying a solution of the intermediate controlled release layer to the drug-loading layer; and (c) applying a solution of the controlled release layer of the casing to the intermediate controlled release layer; wherein steps (a) to (c) This is achieved by spray granulation under a condition that the introduction air temperature is from 28 ° C to 38 ° C by a ball type granulator.