TWI394594B - Pharmaceutical tablet composition and manufacturing method thereof - Google Patents

Description

Tablet pharmaceutical composition and preparation method thereof

The present invention relates to a tablet pharmaceutical composition and a method for producing the same, and more particularly to a tablet pharmaceutical composition using hydroxypropylmethylcellulose and povidone SR as a sustained release carrier and a process for producing the same.

In general, the tablet process is formed by placing the granules or powder into a space of a mold and applying pressure. The multi-layer tableting process is formed by applying pressure to the second layer of granules or powder after pressure molding. By analogy, repeat the same steps to make a multi-layer ingot. Wherein, the double-layer tablet is a dosage form comprising two layers of granular powder; therefore, the two-layer dosage form can be separately designed into different functions or release mechanisms as needed, and then two layers of different functions and/or Or the drug layer of the release mechanism is combined.

In terms of the pharmacological release mechanism, the fast-acting tablet dosage form generally means that the tablet has a rapid disintegration after taking it, and the highest dissolution concentration is obtained in about 1 to 2 hours; on the other hand, the continuous medicinal agent layer has A dosage form for delaying, controlling, and sustained release, which means that the tablet composition contains a polymer which can delay the release of the drug to control the dissolution rate and concentration of the drug, and the polymer comprises a synthetic cellulose. Wait. In addition, commercial synthetic starch products or mixed products are also available as an option.

Furthermore, in China Patent Publication No. 570812, a slower dissolution curve is achieved by a sustained medicinal layer made of a high proportion of palm wax, the technical feature of which consists of a continuous medicinal layer and a quick-acting drug layer. Among the two-layer tablets, the tablets are made from 59 to 81% palm wax, so the in vitro dissolution test curve of the continuous drug layer is slower than the general sustained drug effect tablet (Sudafed 12 Hour 120 mg). The release effect is used to achieve a slower dissolution curve and its process feasibility than the general sustained efficacy tablet.

However, among the commonly used excipient manuals, palm wax is poorly soluble in water; therefore A typical use is a film coating process glazing agent which, although used alone or in combination with other excipients, is a sustained release composition, but in the general process, the recommended ratio of palm wax is between 10 and 50%. Therefore, a higher proportion of palm wax is used as a continuous medicinal formula. Although the dissolution of the sustained medicinal layer is slower, the excessively high palm wax makes the continuous medicinal layer hard and hardly soluble in water. Disintegration may not occur during the dissolution process, which may cause the tablet to be hard and not change in its shape even after 12 hours of dissolution during the dissolution test, so that it may cause gastrointestinal damage caused by peristalsis in the human body.

In summary, it is currently desired to develop a two-layer tablet pharmaceutical composition whose sustained release layer has a relatively long lasting release property and that the dosage form hardness is not excessively hard.

In view of the above problems, it is an object of the present invention to provide a pharmaceutical composition of a tablet having a sustained release layer, which comprises hydroxypropylmethylcellulose and a povidone SR as a component of a sustained release layer, which is relatively long. The sustained release properties of the effect, and the hardness of the dosage form is not excessively hard.

One of the objects of the present invention is to provide a pharmaceutical composition of a tablet having a sustained release layer comprising hydroxypropyl methylcellulose having a viscosity of 80,000 to 120,000 centipoise, which has both sustained release properties and avoids formation of excessive hardness. Formulation.

In order to achieve the above object, a pharmaceutical composition of a tablet, which may be a single layer or a double layer, the double-layer tablet comprises a quick release layer and a sustained release layer each having an active ingredient and an excipient, wherein The release layer further comprises a sustained release carrier, and the sustained release carrier comprises at least monohydroxypropylmethylcellulose and a polyvinylpyrrolidone, wherein the hydroxypropylmethylcellulose has a viscosity of 80,000 to 120,000 centipoise, and the polyvinylpyrrolidone is Kollidon SR, which accounts for 10 to 17% of the sustained release layer.

A method of making a bilayer tablet pharmaceutical composition, first providing a quick release layer comprising a first active ingredient and a rapid release carrier. Next, a second active ingredient, a sustained release carrier is provided to form a mixture, wherein the sustained release carrier comprises at least monohydroxypropylmethylcellulose and a polyvinylpyrrolidone, wherein the viscosity of the hydroxypropylmethylcellulose is about From 80,000 to 120,000 centipoise, polyvinylpyrrolidone is Kollidon SR, which accounts for 10 to 17% of the sustained release layer. The mixture is subjected to a first granulation step to obtain a plurality of first particles. The first particles are subjected to a second granulation step to obtain a sustained release layer. Finally, the tablet is quickly released and the sustained release layer is applied to obtain a bilayer tablet pharmaceutical composition.

In order to achieve the above object, a single layer tablet pharmaceutical composition comprises an active ingredient and a sustained release carrier. The sustained release carrier comprises at least hydroxypropylmethylcellulose (Hypromellose) and a polyvinylpyrrolidone (polyvinylpyrrolidone), wherein the hydroxypropylmethylcellulose has a viscosity of 80,000 centipoise to 120,000 centipoise, and the polyvinylpyrrolidone is a polydimensional A ketone (Kollidon) SR which accounts for 10 to 17% of the sustained release layer. The method of manufacture comprises providing an active ingredient, a sustained release carrier, to form a mixture, wherein the sustained release carrier comprises at least monohydroxypropylmethylcellulose and a povidone SR, wherein the viscosity of the hydroxypropylmethylcellulose It is about 80,000 to 120,000 centipoise, and polyvinylpyrrolidone is Kollidon SR, which accounts for 10 to 17% of the sustained release layer. The mixture is then subjected to a first granulation step to obtain a plurality of first particles. The first particles are then subjected to a second granulation step to obtain a sustained release layer. Finally, the sustained release layer is compressed to obtain a single layer tablet pharmaceutical composition.

The purpose, technical contents, features, and effects achieved by the present invention will become more apparent from the detailed description of the appended claims.

1 shows a pharmaceutical composition of a two-layer tablet according to an embodiment of the present invention, comprising a fast The release layer 1, a sustained release layer 2, and a film coat layer 3 are used to coat the surfaces of the quick release layer 1 and the sustained release layer 2. The rapid release layer 1 comprises a first active ingredient and a first excipient; the sustained release layer 2 comprises a second active ingredient and a sustained release carrier, wherein the sustained release carrier comprises at least monohydroxypropyl methylcellulose (Hypromellose) And a polyvinylpyrrolidone (polyvinylpyrrolidone). Hydroxypropyl methylcellulose has a viscosity of about 80,000 to 120,000 centipoise, and polyvinylpyrrolidone is Kollidon SR, which accounts for 10 to 17% of the sustained release layer. The film coat layer 3 can improve the appearance or impart protection to increase the hardness of the finished product and isolate the gas, moisture or mechanical force from directly contacting the surface of the tablet.

Hydroxypropyl methylcellulose and polyvinylpyrrolidone, each of which is known as synthetic cellulose, can be used as a sustained release carrier. During the trial, the inventors found that the combined use of hydroxypropyl methylcellulose and polyvinylpyrrolidone delayed the release of the drug to achieve a longer-lasting release. Among them, in one embodiment, in order to achieve a good drug release effect, hydroxypropylmethylcellulose accounts for 25 to 70% of the sustained release layer, and polyvinylpyrrolidone accounts for 5 to 30% of the sustained release layer.

In the present embodiment, when the hydroxypropyl methylcellulose is less than 25%, the ratio of polyvinylpyrrolidone to other excipients is relatively high, and the dissolution curve is very fast at 0 to 4 hours in the previous period, and cannot be reached. Stable and sustained release effect, and the hardness is insufficient, the brittle cracking degree is poor, and it is easy to produce defective products when the film is pressed; when the proportion of hydroxypropyl methylcellulose is higher than 70%, relatively, polyvinylpyrrolidone The ratio is low and the specific gravity is relatively light. Even after two granulation steps, it is lower than 0.4 mg/ml (mg/ml), which tends to cause uneven weight during pressing, which makes it easy to cause technical problems during operation, such as rapid release. The layer is separated from the sustained release layer during the ingot process and the separation is poor, and the dissolution curve is from 8 to In 12 hours, the dissolution is faster. In general, the optimal dissolution curve of the stable sustained release dosage form is close to the binary one-time equation. The embodiment of the present invention discloses that the ratio of the two materials can be adjusted to achieve a dissolution curve close to the binary one-time equation. Further, in a preferred embodiment, the ratio of hydroxypropyl methylcellulose to the sustained release layer is 44 to 54%, and the ratio of polyvinylpyrrolidone to the sustained release layer is 10 to 17%. Among them, hydroxypropylmethylcellulose and polyvinylpyrrolidone are often used as commercial products, such as hydroxypropylmethylcellulose, a commercial product containing Methocel K-type; and polyvinylpyrrolidone Commercially available products include povidone (Kollidon®) SR. Among them, povidone SR is a polyvinylpyrrolidone product treated by adding polyvinyl acetate and polyvinylpyrrolidone.

The sustained release carrier may further comprise other ingredients which delay the release of the effective drug as a conditioning agent or as a filler, such as monohydroxypropylcellulose, or monoethylcellulose.

The rapid release layer and the sustained release layer may include other excipients which are commonly used in the formulation or are frequently used in the prior art, and may include a filler, a binder, a disintegrating agent, a pigment, and a flavor. Agent or a lubricant. Commonly used fillers, such as microcrystalline cellulose, lactose, pregelatinized starch, etc.; commonly used adhesives such as polyvinylpyrrolidone, hydroxypropyl cellulose, etc.; commonly used disintegrating agents such as Coscams sodium , sodium carboxymethyl starch, etc.; commonly used lubricants such as magnesium stearate, sodium stearate, stearic acid crystals and the like. Appropriate excipients can be selected according to the principle of pharmacy to meet the basic requirements of the process and tablets.

The first active ingredient and the second active ingredient in the rapid release layer and the sustained release layer may be pharmacologically effective drugs or pharmaceutically acceptable salts thereof, which may be the same or different. In one embodiment, the first active ingredient may be an antihistamine therapeutic drug or a pharmaceutically acceptable drug thereof The salt, the second active ingredient may be a sympathomimetic drug or a pharmaceutically acceptable salt thereof. Antihistamine efficacy drugs such as Cetirizine, Fexofenadine, Diphenhydramine, Levocetirizine, Meclizine, Hydroxyl Hydroxyzine, or Azelastine. Imitation sympathetic drugs such as Epinephrine, Pseudoephedrine, Dopamine, Methylephedrine phenylpropanolamine, Sibutramine, Amphetamine Amphetamine), or salbutamol fenoterol.

In another embodiment, the first or second active ingredient can be a hypotensive drug or a pharmaceutically acceptable salt thereof, such as Doxazosin, Bisoprolol, or Nifedipine ( Nifedipine).

Referring to Tables 1 to 11, the composition of the pharmaceutical composition of the two-layer tablet according to the embodiment of the present invention is shown, and Table 11 is a preferred embodiment.

In addition, please refer to FIG. 2 and FIG. 3 respectively to show the dissolution curve comparison of the quick release layer and the sustained release layer of an Alaigra-D® 12Hour ER Tablets according to an embodiment of the present invention. The above experiment can refer to the dissolution test method specified by the United States Pharmacopeia (USP), and will not be described here. 2, the pharmaceutical composition of the bilayer tablet of the present invention has similar dissolution effect of the first active ingredient filofenadine in the quick release layer and the 12-hour sustained release tablet of Ai La D; and is known from FIG. The second active ingredient pseudoephedrine in the sustained release layer of the double-layer tablet pharmaceutical composition of the present invention (Pseudoephedrine hydrochloride) is similar to the dissolution effect of Ai La D 12-hour continuous release ingot. Further, the dissolution similarity is further analyzed. From the dissolution similarity (f2) of Table 12 and Table 13, the rapid release layer of the double-layer tablet pharmaceutical composition of the embodiment of the present invention and the Ai La D 12-hour sustained release ingot can be known. The in vitro dissolution of the sustained release layer is similar.

In addition, referring to FIG. 4, an example of the present invention provides a bilayer tablet pharmaceutical composition. Manufacturing method. Step S1 provides a quick release layer comprising a first active ingredient and a first excipient. The rapid release layer can be produced by a general tablet preparation method, including but not limited to direct mixing, dry, or The steps of wet granulation and the like are not described herein.

The sustained release layer is prepared by the step S2 of providing a second active ingredient, a sustained release carrier, to form a mixture, wherein the sustained release carrier comprises at least monohydroxypropylmethylcellulose and a povidone SR, wherein the hydroxypropyl group The viscosity of methyl cellulose is about 80,000 to 120,000 centipoise. Further, in one embodiment, the sustained release carrier further comprises monohydroxypropylcellulose, or monoethylcellulose. Next, in step S3, the mixture is subjected to a first granulation step to obtain a plurality of first particles, and the granulation manner may include, but is not limited to, steps such as wet or dry granulation.

For regranulation, the following steps may be performed. In step S4, the first particles are subjected to a second granulation step to obtain a sustained release layer. In step S5, the tablet release layer and the sustained release layer are pressed to obtain a bilayer tablet pharmaceutical composition.

Wherein, the weight of the particles by the heavy granulation process of the first and second granulation steps is relatively high, so that the stability of the weight during the pressing and the flowability of the particles in the process can be enhanced, and the heavy granulation can be used. In vitro dissolution achieves a more slow effect.

Furthermore, the present invention may further comprise a mixing step between the second granulation step and the tableting step, and a second granulation step to obtain a plurality of second particles, the mixing step comprising adding an excipient to the second particles to form The sustained release layer described above.

Thereafter, in step S5, the tablet rapid release layer and the sustained release layer are obtained to obtain a double-layer tablet pharmaceutical composition; in addition, a suitable film coating material may be dissolved in a suitable solvent, and a film coating process is performed through a film coating machine. A film-coated bilayer tablet pharmaceutical composition is prepared. according to The double-layer tablet pharmaceutical composition prepared by the above steps, wherein the appropriate hydroxypropylmethylcellulose accounts for 25 to 70% by weight of the sustained release layer, and the polyvinylpyrrolidone accounts for 5 to 70% of the sustained release layer. 30%; preferably, hydroxypropyl methylcellulose accounts for 44 to 54% of the sustained release layer, and polyvinylpyrrolidone accounts for 10 to 17% of the sustained release layer.

The present invention has been disclosed above in the formulation of a pharmaceutical composition of a bilayer tablet and a method for producing the same, wherein the sustained release layer described above can be used to manufacture a single layer sustained release tablet pharmaceutical composition, and the formulation and manufacturing method thereof are similar to the above, and thus This will not be repeated here.

In view of the above, one of the features of the present invention is to disclose a pharmaceutical composition of a tablet and a method for producing the same, wherein the rapid release of the drug layer rapidly releases the active ingredient and the sustained release of the drug layer is determined by dissolution, due to the present invention The sustained release layer adopts hydroxypropylmethylcellulose and povidone SR as a sustained release carrier, and thus does not contain a waxy component, so that the appearance of the tablet tends to be soft when the drug is dissolved, and the use of a large amount of wax as a carrier can be improved. May cause damage to the gastrointestinal tract, but also has a long-lasting control equivalent to the use of wax as a sustained release carrier, sustained release of the drug effect to achieve a rapid release layer and a sustained medicinal layer in the sustained release of the 12-hour period with Ai D Similar dissolution ratios and dissolution curves.

The embodiments described above are merely illustrative of the technical spirit and the features of the present invention, and the objects of the present invention can be understood by those skilled in the art, and the scope of the present invention cannot be limited thereto. That is, the equivalent variations or modifications made by the spirit of the present invention should still be included in the scope of the present invention.

1‧‧‧Quick release layer

2‧‧‧Continuous release layer

3‧‧‧ film layer

S1‧‧‧Provide a quick release layer step

S2‧‧‧Providing a second active ingredient, a sustained release carrier, to form a mixture

S3‧‧‧ performing a first granulation step to obtain a plurality of first particles

S4‧‧‧ performs a second granulation step to obtain a sustained release layer

S5‧‧‧Steps for rapid release of the tablet and a sustained release layer to obtain a pharmaceutical composition of the bilayer tablet

1 is a schematic view showing the pharmaceutical composition of a double-layer tablet according to an embodiment of the present invention. Things.

2 shows a rapid release layer dissolution curve alignment with an Ai Lai 12 hour sustained release ingot (Allegra-D® 12Hour ER Tablets) in accordance with an embodiment of the present invention.

Figure 3 shows a comparison of the sustained release layer dissolution profiles of Ai La D 12 hour sustained release ingots in accordance with one embodiment of the present invention.

4 is a schematic flow chart showing a method of producing a pharmaceutical composition of a tablet according to an embodiment of the present invention.

1‧‧‧Quick release layer

2‧‧‧Continuous release layer

3‧‧‧ film layer

Claims (14)

A method for producing a pharmaceutical composition of a tablet comprising: providing a rapid release layer comprising a first active ingredient and a rapid release carrier; providing a second active ingredient, a sustained release carrier to form a mixture, wherein The sustained release carrier comprises at least monohydroxypropylmethylcellulose and a polyvinylpyrrolidone, wherein the hydroxypropylmethylcellulose has a viscosity of about 80,000 to 120,000 centipoise, and the polyvinylpyrrolidone is povidone ( Kollidon) SR, which accounts for 10 to 17% of the sustained release layer; the mixture is subjected to a first granulation step to obtain a plurality of first particles, wherein the first granulation step is dry granulation or wet tempering a granulation process; the first granules are subjected to a second granulation step to obtain a sustained release layer, wherein the second granulation step is performed by a heavy granulation process; and the rapid release layer and the sustained release layer are pressed to obtain The tablet pharmaceutical composition. The method for producing a pharmaceutical composition for a tablet according to claim 1, wherein the povidone SR comprises polyvinyl acetate and polyvinylpyrrolidone. The method for producing a pharmaceutical composition of a tablet according to claim 1, wherein the sustained release carrier further comprises hydroxypropylcellulose or ethylcellulose. The method for producing a pharmaceutical composition for a tablet according to claim 1, wherein the hydroxypropylmethylcellulose accounts for 25 to 70% of the sustained release layer. The method for producing a pharmaceutical composition for a tablet according to claim 1, wherein the hydroxypropylmethylcellulose accounts for 44 to 54% of the sustained release layer. The method for producing a bilayer tablet pharmaceutical composition according to claim 1, further comprising a mixing step between the second granulating step and the tableting step, the mixing step comprising adding an excipient to the sustained release In the layer. The method for producing a pharmaceutical composition of a double-layer tablet according to claim 1, wherein the first active ingredient is phenofenadine or a pharmaceutically acceptable salt thereof, and the second active ingredient is a pseudoephedrine Or a pharmaceutically acceptable salt thereof. A method for producing a sustained release tablet pharmaceutical composition comprising: providing an active ingredient, a sustained release carrier to form a mixture, wherein the sustained release carrier comprises at least monohydroxypropylmethylcellulose and a polyvinylpyrrolidone ( Polyvinylpyrrolidone), wherein the hydroxypropyl methylcellulose has a viscosity of about 80,000 to 120,000 centipoise, and the polyvinylpyrrolidone is a Kollidon SR, which accounts for 10 to 17% of the sustained release layer; The mixture is subjected to a first granulation step to obtain a plurality of first granules, wherein the first granulation step is a dry granulation or wet granulation procedure; the first granules are subjected to a second granulation step to obtain a A sustained release layer wherein the second granulation step employs a heavy granulation procedure; and the sustained release layer is compressed to obtain the sustained release tablet pharmaceutical composition. The method for producing a sustained release tablet pharmaceutical composition according to claim 8, wherein the povidone SR comprises polyvinyl acetate and polyvinylpyrrolidone. The method for producing a sustained release tablet pharmaceutical composition according to claim 8, wherein the sustained release carrier further comprises hydroxypropylcellulose or ethylcellulose. The method for producing a sustained release tablet pharmaceutical composition according to claim 8, wherein the hydroxypropyl group Methylcellulose accounts for 25 to 70% of the sustained release layer. The method for producing a sustained release tablet pharmaceutical composition according to claim 8, wherein the hydroxypropylmethylcellulose accounts for 44 to 54% of the sustained release layer. The method for producing a sustained release tablet pharmaceutical composition according to claim 8, further comprising a mixing step between the second granulating step and the tableting step, the mixing step comprising adding an excipient to the sustained release In the layer. The method for producing a sustained release tablet pharmaceutical composition according to claim 8, wherein the active ingredient is a pseudoephedrine or a pharmaceutically acceptable salt thereof.