WO2023145870A1

WO2023145870A1 - Formulation composition, formulation, and method for producing formulation composition

Info

Publication number: WO2023145870A1
Application number: PCT/JP2023/002613
Authority: WO
Inventors: 元晴藤崎; 彰木村
Original assignee: 住友精化株式会社
Priority date: 2022-01-31
Filing date: 2023-01-27
Publication date: 2023-08-03

Abstract

The present invention provides: a formulation composition that makes it possible to easily obtain a formulation which has high hardness and is easily produced; a formulation that includes said composition; and a method for producing the formulation composition.　A formulation composition according to the present invention comprises particles containing a filler, an active component, and a binding agent, wherein: the particles contain the filler and the active component in an amount of 80-95 mass% with respect to the total mass of the filler, the active component, and the binding agent; the content of the filler is 1-94 mass% with respect to the total mass of the filler, the active component, and the binding agent; and the coverage ratio of the binding agent on the surface of the particles is not less than 20%.

Description

Pharmaceutical compositions and formulations, and methods for producing pharmaceutical compositions

The present invention relates to pharmaceutical compositions and formulations, and methods for producing pharmaceutical compositions.

It is known that formulations typified by controlled release formulations that release drugs can be obtained by various methods. For example, a raw material containing an active ingredient and a binder is mixed and prepared, the resulting mixture is granulated to form particles (granules), and the granules are tableted to produce a formulation. Know how to get.

Methods such as wet granulation and dry granulation are known as methods for obtaining the above-mentioned granules. A method of kneading and granulating raw materials has been proposed. Such a method requires a small energy load during production, and can be applied to raw materials containing drugs that are sensitive to moisture.

Japanese Patent Application Laid-Open No. 2008-540540

However, since conventional particles (granules) containing an active ingredient and a binder do not have sufficient hardness, they tend to be unsuitable as formulations. In order to improve the hardness, methods such as changing the manufacturing conditions such as twin-screw extrusion and adjusting the amount of the binder are conceivable, but in this case, the granulation properties may deteriorate, making it difficult to obtain a formulation. There was a problem of becoming It is also conceivable to adjust the hardness by changing the content ratio of the active ingredient, but in this case, the amount of the active ingredient is fixed, making it difficult to adjust the drug concentration. There was also

The present invention has been made in view of the above, and is easy to manufacture, and a pharmaceutical composition that can easily obtain a formulation having a high hardness, a formulation containing the composition, and the pharmaceutical composition The object is to provide a manufacturing method.

As a result of intensive studies aimed at achieving the above object, the inventors of the present invention have found that the above object can be achieved by setting the filler, active ingredient and binder to predetermined amounts, and by setting the binder coverage to a predetermined ratio. and completed the present invention.

That is, the present invention includes, for example, the subject matter described in the following sections.
Item 1
A pharmaceutical composition comprising particles comprising a filler, an active ingredient and a binder,
The particles contain the filler and the active ingredient at a ratio of 80% by mass or more and 95% by mass or less with respect to the total mass of the filler, the active ingredient and the binder, and the content of the filler is 1 to 94% by weight relative to the total weight of the filler, the active ingredient, and the binder;
A composition for pharmaceutical preparation, wherein the coating rate of the binder on the particle surface is 20% or more.
Item 2
Item 2. The pharmaceutical composition according to Item 1, wherein the binder is a water-soluble polymer.
Item 3
The binder is selected from the group consisting of polyethylene oxide, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polymethacrylate, copolymers of N-vinylpyrrolidone and vinyl acetate, and copolymers of N-vinylcaprolactam, vinyl acetate and ethylene glycol. Item 3. The composition for formulation according to Item 1 or 2, which is at least one selected.
Item 4
Item 4. The pharmaceutical composition according to any one of Items 1 to 3, wherein the binder has a mass average molecular weight of 1000000 g/mol or less.
Item 5
Item 5. The pharmaceutical composition according to any one of Items 1 to 4, wherein the binder is polyethylene oxide having a mass average molecular weight of 50000 g/mol or more and 1000000 g/mol or less.
Item 6
A formulation comprising the pharmaceutical composition according to any one of Items 1 to 5.
Item 7
A method for producing the pharmaceutical composition according to any one of Items 1 to 5,
A step 1 of kneading and granulating a mixture containing an active ingredient and a binder in a barrel by a twin-screw extrusion method,
The temperature in the barrel is 140° C. or less,
The weight average molecular weight of the binder is 1000000 g/mol or less,
The mixture contains the filler and the active ingredient in a ratio of 80% by mass or more and 95% by mass or less with respect to the total mass of the filler, the active ingredient and the binder,
A method for producing a pharmaceutical composition, wherein the content of the filler is 1 to 94.0% by mass with respect to the total mass of the filler, the active ingredient and the binder.

The pharmaceutical composition of the present invention is easy to manufacture, and a formulation having high hardness can be easily obtained.

1 is a schematic diagram showing an example of a screw used in manufacturing the pharmaceutical composition of the present invention. FIG. It is the schematic which shows an example of the screw used in the Example.

Hereinafter, embodiments of the present invention will be described in detail. In this specification, the expressions "contain" and "include" include the concepts of "contain", "include", "substantially consist of" and "consist only of".

In the numerical ranges described stepwise in this specification, the upper limit or lower limit of the numerical range at one stage can be arbitrarily combined with the upper limit or lower limit of the numerical range at another stage. In the numerical ranges described herein, the upper and lower limits of the numerical ranges may be replaced with values shown in Examples or values that can be uniquely derived from Examples. Further, in this specification, a numerical value connected with "-" means a numerical range including numerical values before and after "-" as lower and upper limits.

1. Pharmaceutical composition The pharmaceutical composition of the present invention contains particles comprising a filler, an active ingredient and a binder, and the particles account for the total weight of the filler, the active ingredient and the binder to the filler. And the active ingredient is contained in a ratio of 80% by mass or more and 95% by mass or less, and the content of the filler is 1 to 94% by mass with respect to the total mass of the filler, the active ingredient, and the binder, The coverage of the binder on the particle surface is 20% or more.

The pharmaceutical composition of the present invention is easy to produce, can easily yield a formulation with high hardness, and is suitable as a raw material for producing a formulation. In addition, tablets prepared using the pharmaceutical composition of the present invention have high hardness even when the drug concentration is varied widely. Therefore, the pharmaceutical composition of the present invention is suitable as a raw material for producing a formulation with high hardness.

The type of filler is not particularly limited, and for example, a wide range of pharmaceutically acceptable fillers used in formulations can be cited.

Examples of fillers include granulated sugar, dextrate, dextrin, dextrose, lactose, lactose monohydrate, mannitol, microcrystalline cellulose, sorbitol, sucrose, talc, and inorganic salts. Examples of inorganic salts include alkali metal salts such as sodium chloride.

Above all, the filler preferably has a melting point equal to or higher than the temperature of the binder, and particularly preferably sodium chloride or lactose monohydrate.

The type of active ingredient is not particularly limited, and a wide range of known active ingredients can be applied. Examples of active ingredients include drugs such as acetaminophen, which are used as antipyretics and analgesics.

The active ingredient can be produced by a known method, or can be obtained from commercial products.

The type of binder is not particularly limited, and for example, binders used in formulations can be widely applied in the present invention. In particular, various polymer materials having a mass average molecular weight of 1,000,000 g/mol or less can be used as binders. easier. Various polymeric materials having a weight average molecular weight of 1000000 g/mol or less may be homopolymers or copolymers.

The binder is preferably a water-soluble polymer because it has excellent solubility in water. Examples of such water-soluble polymers include polyvinylpyrrolidone, copolymers of N-vinylpyrrolidone and vinyl acetate, copolymers of N-vinylcaprolactam, vinyl acetate and ethylene glycol, and copolymers of N-vinylpyrrolidone and vinyl propionate. , cellulose esters, cellulose ethers, hydroxyalkylcelluloses (e.g. hydroxypropylcellulose, hydroxypropylmethylcellulose), cellulose phthalates, cellulose succinates, polyalkylene oxides (e.g. polyethylene oxide, polypropylene oxide), copolymers of ethylene oxide and propylene oxide , polyacrylates, polymethacrylates, polyacrylamides, vinyl acetate polymers, polyvinyl alcohols, oligosaccharides, polysaccharides, and the like.

The binder is from the group consisting of polyethylene oxide, hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone, polymethacrylates, copolymers of N-vinylpyrrolidone and vinyl acetate, and copolymers of N-vinylcaprolactam, vinyl acetate and ethylene glycol. At least one selected is more preferable. In this case, the particles (also referred to as granules) are easily formed (that is, the composition is excellent in granulation properties), which facilitates the production of the pharmaceutical composition and facilitates the preparation of a highly rigid formulation.

The binder is more preferably at least one selected from the group consisting of polyethylene oxide and hydroxypropyl cellulose, in terms of particularly excellent granulation properties at low temperatures and easy preparation of formulations with higher hardness. is particularly preferred. In particular, when the binder is polyethylene oxide, granules (particles) with excellent moldability are easily obtained even when kneading at a lower temperature. Easy to prepare formulations.

The weight average molecular weight of the binder is preferably 50000 g/mol or more and 1000000 g/mol or less. In this case, granulation is facilitated in the production of the composition for pharmaceutical preparation, and it is easy to prepare a pharmaceutical composition with high hardness. The weight average molecular weight of the binder is more preferably 80000 g/mol or more, further preferably 100000 g/mol or more, and more preferably 850000 g/mol or less, and 750000 g/mol or less. is more preferable, and 300000 g/mol or less is particularly preferable.

A preferable binder is polyethylene oxide having a mass average molecular weight of 50000 g/mol or more and 1000000 g/mol or less, and particularly preferably polyethylene oxide having a mass average molecular weight of 100000 g/mol or more and 300000 g/mol or less.

The binder can be produced by a known method, or can be obtained from commercial products. For example, when the binder is a polyalkylene oxide, the polyalkylene oxide can be produced by polymerization of the alkylene oxide in the presence of a catalyst.

The pharmaceutical composition of the present invention can be composed mainly of particles containing the filler, the active ingredient, and the binder. For example, the pharmaceutical composition of the present invention can contain particles containing the filler, the active ingredient, and the binder in an amount of 50% by mass or more, preferably 80% by mass or more, and more preferably 90% by mass. Above, more preferably 95% by mass or more, particularly preferably 99% by mass or more. The pharmaceutical composition of the present invention can also consist of only particles containing the filler, the active ingredient, and the binder.

The filler contained in the particles may be of one type, or may be of two or more types. Similarly, the active ingredients contained in the particles can be one, or two or more. Also, the binder contained in the particles can be of one type, or can be of two or more types.

Said particles may contain other ingredients as long as said filler, said active ingredient and said binder are included, and said particles consist only of said filler, said active ingredient and said binder. is also possible. Other ingredients include, for example, various additives contained in known formulations. Examples of such additives include excipients, diluents, lubricants, dyes, pigments, etc. Specific examples include silica such as Aerosil.

When the particles contain other components (for example, the additives), the content of the other components is preferably 10% by mass or less, more preferably 10% by mass or less, based on the total mass of the filler, the active ingredient, and the binder. is 5% by mass or less, more preferably 1% by mass or less, and particularly preferably 0.5% by mass or less.

As described above, the particles contain 80% by mass or more of the filler and the active ingredient with respect to the total mass of the filler, the active ingredient, and the binder (that is, the particles contain the filler, the active ingredient, and 20% by mass or less of the binder with respect to the total mass of the binder). This facilitates the production of the pharmaceutical composition, and facilitates the preparation of a highly rigid formulation.

The particles contain 80% by mass or more and 95% by mass or less of the filler and the active ingredient with respect to the total mass of the filler, the active ingredient, and the binder (that is, the particles contain the filler, the active ingredient, and the 5% by mass or more and 20% by mass or less of the binder based on the total mass of the components and the binder). This facilitates the production of the pharmaceutical composition, and facilitates the preparation of a highly rigid formulation. When the content of the binder in the particles exceeds 20% by mass with respect to the total mass of the filler, the active ingredient and the binder, it becomes difficult to form a formulation from the pharmaceutical composition, such as a tablet. However, even if it can be formulated, it is difficult to have a high hardness. In addition, from the viewpoint of excellent granulation properties during production, the content of the binder in the particles should be 7% by mass or more with respect to the total mass of the filler, the active ingredient, and the binder. is more preferable, and 7.5% by mass or more is even more preferable.

In addition, in the particles, the content ratio of the filler is 1 to 94% by mass with respect to the total mass of the filler, active ingredient, and binder. This facilitates the production of the pharmaceutical composition, facilitates the preparation of a highly rigid formulation, and prevents the granulation and hardness of the formulation from being impaired even when the drug concentration is varied widely. The content of the filler is preferably 22.5% by mass or more and preferably 91.5% by mass or less with respect to the total mass of the filler, active ingredient and binder.

The shape of the particles is not particularly limited, and may be, for example, spherical, ellipsoidal, irregular, or the like, or may be agglomerated particles formed by aggregating a plurality of particles.

The size of the particles is also not particularly limited, and can be adjusted as appropriate according to the intended formulation, for example. For example, the particles preferably have a median particle size of 100 to 500 μm.

As described above, the particles have a surface coverage of the binder of 20% or more. This makes it possible to prepare formulations with high hardness.

In the present invention, the coverage can be measured by an ATR method (total reflection measurement method) using a Fourier transform infrared spectrophotometer using particles as a measurement sample, or by a method combining the ATR method and EDS. . Here, the case where the filler is an organic compound and the case where the filler is an inorganic compound or a mixture of an inorganic compound and an organic compound will be described separately.

(When the filler is an organic compound)
When the filler is an organic compound, the coverage can be specifically measured by the following method. 6 types of mixtures are prepared by arbitrarily changing the mass ratio of the same active ingredient and binder as the active ingredient and binder contained in the measurement sample and mixing, and Fourier transform infrared spectrophotometry is performed for each mixture Absorbance is measured using a meter (JASCO Corporation), and a calibration curve is created from the absorbance ratios in the absorption bands characteristic of the active ingredient and the binder, respectively. In addition, 6 types of mixtures were prepared by arbitrarily changing the mass ratio of the same filler component and binder as the filler component and binder contained in the measurement sample and mixing, and Fourier transform infrared Absorbance is measured using a spectrophotometer (JASCO Corporation), and a calibration curve is created from the absorbance ratios in the characteristic absorption bands of the filler component and the binder, respectively. For example, if the active ingredient is acetaminophen, the filler is lactose monohydrate, and the binder is polyethylene oxide, the characteristic absorption bands are at 1650 cm ⁻¹ , 3333 cm ⁻¹ and 2880 cm ⁻¹ , respectively. Create a calibration curve from the absorbance ratio of Next, the absorbance is measured using a Fourier transform infrared spectrophotometer (JASCO) for the particles that are the measurement sample, and the measured absorbance is substituted into the function related to the calibration curve, thereby obtaining the active ingredient and By calculating the ratio of binder and the ratio of filler to binder respectively, the ratio of binder to active ingredient, filler and binder is calculated. This existence ratio is defined as the particle coverage.

(When the filler is an inorganic compound, or a mixture of an inorganic compound and an organic compound)
When the filler is an inorganic compound, or when an inorganic compound and an organic compound are mixed, the coverage can be specifically measured by the following method. For the coverage when the inorganic compound is included in the filler component of the particles, the amount of the inorganic compound is quantified using an energy dispersive X-ray spectrometer (EDS) mounted on a scanning electron microscope (JEOL Ltd., JSM-IT200LA). can be calculated by Specifically, the same inorganic compound, active ingredient and binder as the inorganic compound, active ingredient and binder contained in the measurement sample are mixed by arbitrarily changing the mass ratio to prepare three types of mixtures. EDS is used to measure the characteristic X-ray intensity of the mixture, and a calibration curve is created from the characteristic X-ray intensities of the elements contained in the inorganic compound. For example, when the inorganic compound is sodium chloride, the characteristic X-ray intensities of sodium and chlorine are measured, and a calibration curve is created from the sum of the characteristic X-ray intensities of sodium and chlorine. Next, the characteristic X-ray intensity of the particles, which are the measurement samples, is measured using EDS, and the measured characteristic X-ray intensity of the inorganic compound is substituted into the function related to the calibration curve, thereby obtaining the The existence ratio of the inorganic compound that is included is calculated. The abundance ratio of the binder is calculated from the ratio of the abundance ratio of the inorganic compound to the abundance ratio of the active ingredient and the binder calculated by the ATR method. Let this existence ratio be a coverage. It should be noted that the "ratio of active ingredient and binder calculated by the ATR method" is the same method as described in the above "When the filler is an organic compound" (however, no filler is used), and the active ingredient and The ratio of binder to binder can be calculated.

The coverage of the binder on the particle surface is preferably 20% or more, more preferably 25% or more, and even more preferably 30% or more. The coverage of the binder on the particle surface is, for example, preferably 70% or less, more preferably 60% or less.

Here, when the content of the binder contained in the particles is P% by mass and the coverage is C%, it is preferable that P<C. In this case, it means that the particles have more binder distribution near the surface than inside the particles, which makes the pharmaceutical composition of the invention more likely to form a harder formulation. . In short, the higher concentration of binder near the surface of the particles than in the interior facilitates the formulation compositions of the present invention to form harder formulations.

The value of C is preferably 1.5 times or more, more preferably 2 times or more, even more preferably 2.5 times or more, particularly 3 times or more, as compared to the P value. preferable. Also, the value of C is preferably 9.5 times or less, more preferably 8 times or less, the value of P.

The content ratio P (% by mass) of the binder contained in the particles can be quantified by the following method using gel permeation chromatography. Four aqueous solutions of the above-mentioned particles are prepared with arbitrarily changed binder concentrations. The area of each peak is measured by gel permeation chromatography, and a standard curve of binding agent concentration and peak area is constructed. Next, by preparing an aqueous solution of the particles as a measurement sample and measuring the peak area, the binder concentration in the aqueous solution is calculated from the calibration curve. The binder content P can be calculated from the binder mass in the aqueous solution calculated from the obtained binder concentration and the mass ratio of the particles used to prepare the aqueous solution. The binder content P measured by this method can be considered to correspond to the content of the binder contained in the mixture used in the production.

Since the pharmaceutical composition of the present invention contains the particles, the pharmaceutical composition (e.g., tablet) from which the composition is prepared has high hardness, for example, can have a compression strength of 2 MPa or more. It is.

In particular, when the particle contained in the pharmaceutical composition of the present invention has a structure in which the concentration of the binder near the surface is higher than that inside the particle, the surface is bound even if the concentration of the active ingredient as a whole is increased. Due to the high distribution of agents, high hardness is maintained due to the large amount of binder present on the surface despite the high concentration of active ingredient. Therefore, in one aspect of the pharmaceutical composition of the present invention, it is possible to prepare a formulation having a high concentration of the active ingredient while having a high hardness. It becomes easy to demonstrate.

As described above, the pharmaceutical composition of the present invention can contain other ingredients as long as it contains the particles. In addition, the pharmaceutical composition of the present invention may contain a separate binding agent independently of the particles, and may contain a separate active ingredient. Other ingredients include various ingredients as long as the effects of the invention are not impaired. The pharmaceutical composition of the present invention may consist only of the particles.

2. Method for producing the pharmaceutical composition The method for producing the pharmaceutical composition of the present invention is not particularly limited, and for example, a wide range of known methods for producing pharmaceutical compositions can be employed. In particular, as described later, it is preferable to prepare the pharmaceutical composition through step 1 using a twin-screw extrusion method for the particles. In this case, the coating rate is easily adjusted to a desired range, and The surface tends to form particles with a large distribution of binder.

The method for producing the pharmaceutical composition of the present invention can comprise step 1 of kneading and granulating a mixture containing a filler, an active ingredient, and a binder in a barrel, for example, by twin-screw extrusion. In the production method including step 1, the temperature in the barrel is 140° C. or less, the binder has a weight average molecular weight of 1000000 g/mol or less, and the mixture comprises the filler, the active ingredient and the binding agent. The total mass of the filler and the active ingredient is 80% by mass or more with respect to the total mass of the agent.

In step 1, a mixture containing a filler, an active ingredient, and a binder can be used as raw materials. The filler, active ingredient and binder contained in the raw material are the same as the filler, active ingredient and binder contained in the pharmaceutical composition of the present invention described above. Therefore, various polymer materials having a weight average molecular weight of 1000000 g/mol or less are used as binders. The binder is a polymer having a mass average molecular weight of 1,000,000 g/mol or less, so that even though the temperature inside the barrel is low (140° C. or less), a formulation with high hardness can be prepared. can get things.

The binder is from the group consisting of polyethylene oxide, hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone, polymethacrylates, copolymers of N-vinylpyrrolidone and vinyl acetate, and copolymers of N-vinylcaprolactam, vinyl acetate and ethylene glycol. At least one selected is more preferable. In this case, even if the temperature inside the barrel is low, the pharmaceutical composition can be easily granulated (that is, the granulation properties are excellent).

From the viewpoint of particularly excellent granulation properties, the binder is preferably a polyethylene oxide having a mass average molecular weight of 50000 g/mol or more and 1000000 g/mol or less, more preferably 100000 g/mol or more and 300000 g/mol or less. is particularly preferred.

The binder used as a raw material can be manufactured by a known method, or can be obtained from commercial products. For example, when the binder is a polyalkylene oxide, the polyalkylene oxide can be produced by polymerization of the alkylene oxide in the presence of a catalyst.

Each of the fillers and active ingredients contained in the raw materials used in the present invention can be of one type alone, or can be of two or more types. Similarly, the raw materials used in the present invention may contain one binder, or two or more binders.

The raw materials used in the method for producing the pharmaceutical composition of the present invention may contain other ingredients as long as they contain a mixture of the filler, the active ingredient and the binder. It is also possible to consist solely of said mixture (ie said active ingredient and said binder). Examples of such other components include various additives contained in known formulations. Examples of such additives include excipients, diluents, lubricants, dyes, pigments, etc. Specific examples include silica such as Aerosil.

When the raw material contains other components (for example, the additive) in addition to the mixture, the content of the other component is preferably 10% by mass or less with respect to the total mass of the filler, the active ingredient, and the binder. , more preferably 5% by mass or less, still more preferably 1% by mass or less, and particularly preferably 0.5% by mass or less.

The mixture contained in the raw material contains the filler and the active ingredient at a ratio of 80% by mass or more and 95% by mass or less with respect to the total mass of the filler, the active ingredient and the binder (i.e., the mixture contains the binder in a ratio of 5% by mass or more and 20% by mass or less with respect to the total mass of the filler, the active ingredient and the binder). This makes it easy to granulate the composition for formulation even when the temperature in the barrel is low, and to prepare a formulation with high hardness. If the content of the binder in the mixture exceeds 20% by mass with respect to the total mass of the filler, the active ingredient and the binder, it becomes difficult to form a formulation from the pharmaceutical composition. However, even if it can be formulated, it is difficult to have a high hardness. From the viewpoint of excellent granulation properties, the content of the binder in the mixture is preferably 7% by mass or more with respect to the total mass of the filler, the active ingredient and the binder, and 7.5 % or more is more preferable.

The mixture more preferably contains 85% by mass or more of the filler and the active ingredient with respect to the total mass of the filler, the active ingredient and the binder. Further, in the mixture, the content ratio of the filler and the active ingredient is more preferably 93% by mass or less, more preferably 92.5% by mass or less, relative to the total mass of the filler, the active ingredient and the binder. is particularly preferred.

The method of preparing the raw material containing the mixture is not particularly limited. For example, a raw material containing the mixture can be prepared by mixing the filler, the active ingredient, and the binder in a predetermined ratio. In preparing the raw materials, if necessary, ingredients other than fillers, active ingredients, and binders can be mixed with the raw materials. The raw material containing the mixture can be prepared, for example, by mixing means using a known mixer or the like.

In addition, in the mixture, the content ratio of the filler is 1 to 94% by mass with respect to the total mass of the filler, active ingredient, and binder. This facilitates the production of the pharmaceutical composition, facilitates the preparation of a highly rigid formulation, and prevents the granulation and hardness of the formulation from being impaired even when the drug concentration is varied widely. The content of the filler is preferably 22.5% by mass or more and preferably 91.5% by mass or less with respect to the total mass of the filler, active ingredient and binder.

(Step 1)
Step 1 is a step of kneading and granulating raw materials containing the mixture in a barrel by a twin-screw extrusion method. Granules containing an active ingredient and a binder can be obtained by such Step 1.

In process 1, raw materials are kneaded and granulated using a twin-screw extruder. As the twin-screw extruder, for example, widely known twin-screw extruders can be used.

The type of screw provided in the twin-screw extruder used in step 1 is also not particularly limited, and a wide range of known screws can be used.

Generally, a screw is composed of a Pre-Conditioning section (also referred to as a transfer section), an Agglomeration section (also referred to as a kneading section), and a Breakage section (also referred to as a crushing section). The screw used in the present invention preferably includes at least an Agglomeration section (kneading section), and more preferably includes all of a Pre-Conditioning section (transfer section), an Agglomeration section (kneading section) and a Breakage section (crushing section). . If the screw does not have a Breakage section (pulverization section), it is preferable to provide a pulverization step after twin-screw extrusion.

In particular, in the present invention, it is preferable that the kneading section is composed of a kneading type screw and the rest of the kneading section is composed of a so-called full flight screw. In this case, even if the temperature in the barrel is low, it is easy to granulate the composition for pharmaceutical preparation, and it is easy to prepare a pharmaceutical composition with high hardness.

The kneading section preferably occupies 15 to 30% of the length of the entire screw. In this case, even if the temperature in the barrel is low, it is easy to granulate the composition for pharmaceutical preparation, and it is easy to prepare a pharmaceutical composition with high hardness.

In addition, the kneading portion is positioned at 0 to 90% when the tip side (granule outlet side) of both ends of the screw is 0% and the rear end side (raw material input side or raw material inlet side) is 100%. It is preferable that it is arranged at any site within the range of Here, the tip side of the screw means the downstream side in the flow direction of the raw material, and the rear end side of the screw means the upstream side in the flow direction of the raw material.

Especially in the present invention, it is preferable to use the screw shown in FIG. In this case, even if the temperature in the barrel is low, it is easy to granulate the composition for pharmaceutical preparation, and it is easy to prepare a pharmaceutical composition with high hardness.

FIG. 1 is a schematic diagram of a screw that can be suitably used in the method for producing a pharmaceutical composition of the present invention. In the screw shown in FIG. 1, for example, there is a notation "36/24", where "36" means the length (mm) of each unit of the screw, and "24" means that the screw has made one rotation. Sometimes it means the length (mm) that the wing advances, the so-called lead. In addition, there is a notation "28/5R45 °", in this notation, "28" means the length (mm) of each unit of the screw, "5" means the number of kneading discs, "45 ° ' means the angle of the kneading disc, and 'R' means that the kneading disc is attached to the right hand. There is a notation of "7/14 notch", in this notation, "7" means the length (mm) of each unit of the screw, and "14" is the length (mm) that the blade advances when the screw rotates once. , means a so-called lead, and "notched" means a notched screw. In addition, even if there is no notation of R in FIG. 1, it means that it is a right-handed screw.

In step 1, the conditions for kneading the raw materials in the barrel of the extruder are not particularly limited as long as the temperature in the barrel is 140°C or less. By kneading the raw materials at a temperature in the barrel of 140° C. or less, the composition for pharmaceutical preparation can be granulated, and a highly rigid preparation can be prepared. Moreover, by kneading the raw materials at a temperature in the barrel of 140° C. or lower, decomposition of the active ingredient, that is, the drug can be suppressed. Since a plurality of barrels are usually used, the temperature inside all the barrels is set to 140° C. or lower in the present invention.

In step 1, the temperature in the barrel is preferably 120°C or lower, more preferably 110°C or lower, even more preferably 100°C or lower, and particularly preferably 90°C or lower. In addition, when polyalkylene oxide or hydroxyalkyl cellulose, especially polyethylene oxide or hydroxypropyl cellulose, is used as a binder, granulation is excellent even at 100°C or less, and it is possible to prepare a formulation with higher hardness. becomes.

In step 1, the temperature inside the barrel is not particularly limited, and is, for example, 20°C or higher, preferably 30°C or higher, more preferably 40°C or higher.

In the twin-screw extrusion method, the number of revolutions of the screw is not particularly limited, and, for example, the same conditions as in the method of producing a pharmaceutical composition by a known twin-screw extrusion method can be used. For example, the screw speed can be 50-500 rpm (same for commercial screws).

By twin-screw extruding the raw material containing the mixture, particles (granules) containing a filler, an active ingredient, and a binder can be obtained. The obtained granules can be pulverized if necessary. The pulverization method is not particularly limited, and for example, the granules can be pulverized using a known pulverization means. The granules or the pulverized granules may be classified, if necessary.

3. Formulations The formulations of the present invention include the formulation compositions of the present invention described above. The dosage form of the formulation is not particularly limited, preferably a tablet.

The formulation of the present invention can be obtained, for example, by tableting the pharmaceutical composition of the present invention. In this case the formulation is a tablet. The tableting method is not particularly limited, and for example, it can be performed using a known tableting machine.

Because the formulation of the present invention is formed from the pharmaceutical composition, it has high hardness, for example, a compressive strength of 2 MPa or more. Also, the concentration of the active ingredient contained in the formulation is widely controlled.

In specifying the inventions included in the present disclosure, each configuration (property, structure, function, etc.) described in each embodiment of the present disclosure may be combined in any way. That is, the present disclosure encompasses all subject matter consisting of any combination of each of the combinable features described herein.

The present invention will be described in more detail below with reference to examples, but the present invention is not limited to the embodiments of these examples.

(Example 1)
In a 20 L drum can, acetaminophen (manufactured by Chemexpress) as an active ingredient, sodium chloride (manufactured by Nacalai Tesque) as a filler, and polyethylene oxide (manufactured by Sumitomo Seika Chemicals, mass average molecular weight 160,335 g / mol) as a binder. were mixed in a weight ratio of 10:82.5:7.5 (active:filler:binder) to prepare a mixture. By adding 0.1% Aerosil (manufactured by Evonik) to this mixture and mixing for 150 minutes or more with a blender (manufactured by Misgi, Mazemazeman SKH-40CA: 0.7 rpm) , to obtain a raw material for twin-screw extrusion.

The obtained raw material is fed to a twin-screw extruder (TEM-18SS-10/2V: Toshiba Machine) equipped with a screw shown in FIG. A granulated product is obtained by charging at a supply rate of 8 kg/h, granulating under the conditions of a heating zone 1 temperature of 25° C., a heating zone 2 to 5 temperatures of 40° C., and a screw rotation speed of 200 rpm. rice field. The twin-screw extruder used consisted of 10 barrels, each of which had a length of 75 mm. As shown in Fig. 2, the area from the feed port is zone 0, the area from 75 to 225 mm is heating zone 1, the area from 225 to 375 mm is heating zone 2, and the area from 375 to 525 mm is heating zone 0. 3. An area of 525 to 675 mm was designated as heating zone 4, and an area of 675 to 750 mm was designated as heating zone 5, and the heating temperature was controlled independently for each heating zone. The kneading section is located in the heating zone 3 and the heating zone 4 (shaded area in FIG. 2).

The obtained granules were pulverized with a food processor (ZOJIRUSHI, model BM-RT08) (10 seconds/time × 3 times), and coarse powder was removed with a 32-mesh (500 µm mesh) sieve to obtain granules. A pharmaceutical composition consisting of was obtained.

(Example 2)
A pharmaceutical composition was prepared in the same manner as in Example 2 except that the mass ratio of the active ingredient, filler, and binder was changed to 1:91.5:7.5 (active ingredient: filler: binder). got

(Example 3)
The mass ratio of active ingredient, filler, and binder was changed to 70:22.5:7.5 (active ingredient:filler:binder), and the temperature of heating zones 2-5 was changed to 30°C. A pharmaceutical composition was obtained in the same manner as in Example 1 except for the above.

(Example 4)
A pharmaceutical composition was prepared in the same manner as in Example 1 except that the binder was changed to polyethylene oxide (manufactured by Sumitomo Seika, mass average molecular weight 820,913) and the temperature of heating zones 2 to 5 was changed to 30 ° C. got

(Example 5)
A pharmaceutical composition was obtained in the same manner as in Example 1 except that the filler was changed to lactose monohydrate (manufactured by Fuji Film Wako Pure Chemical Industries) and the temperature of heating zones 2 to 5 was changed to 30 ° C. .

(Comparative example 1)
Example except that the mass ratio of active ingredient, filler, and binder was changed to 10:60:30 (active ingredient:filler:binder) and the temperature of heating zones 2-5 was changed to 30°C. A pharmaceutical composition was obtained in the same manner as in 1.

(Comparative example 2)
A pharmaceutical composition was obtained in the same manner as in Example 1, except that the temperature of heating zones 2 to 5 was changed to 150°C.

(Evaluation method)
<Measurement of hardness of formulation>
The hardness of the formulation was evaluated by measuring the compressive strength of the tablets. Specifically, 500 mg of the pharmaceutical composition (granules) obtained in each of Examples and Comparative Examples was taken, and a tableting machine (Shimadzu Autograph AGS-J) was used to compress the tablet at a tableting pressure of 10 kN. A flat tablet (10.7 mmφ, flat tablet) was produced under the conditions. The thickness of the tablet was measured with a thickness gauge (Tekclock). Using this tablet as a tablet, the hardness was measured using a hardness tester (TBH325 tablet hardness tester manufactured by ERWEKA) under the conditions of a sensitivity of 10 N, a measurement speed of 2.3 mm/s, a measurement pressure of 20 N/s, and a measurement mode of Speed. The hardness measured in this measurement was converted to compressive strength using the following formula.

<Measurement of mass average molecular weight of polyethylene oxide>
The weight average molecular weight of polyethylene oxide was determined by gel permeation chromatography. Specifically, 0.02 g of polyethylene oxide was added to 40 mL of 0.19 M sodium nitrate aqueous solution and dissolved over 3 hours. The solution was filtered using a 0.8 μm membrane filter, and the obtained filtrate was subjected to gel permeation chromatography It was measured by lithography (“HLC-8220GPC” manufactured by Tosoh Corporation, guard column: TSKgel guardcolumn PWXL). In this measurement, size exclusion columns were TSKgel G6000PWXL, TSKgel GMPWXL and TSKgel G3000PWXL, the mobile phase was 0.20 M sodium nitrate aqueous solution, the flow rate was 0.5 mL/min, the column temperature was 40°C, and the differential refractometer temperature was 40°C. , the injection amount was 500 μL, and the measurement time was 90 minutes. Separately, a standard sample of polyethylene oxide having a known mass average molecular weight was measured in the same manner to prepare a calibration curve, and the mass average molecular weight of polyethylene oxide was calculated based on this calibration curve.

<Particle coverage>
(When the filler is an organic compound)
The coverage when the filler is an organic compound was measured by a method using the ATR method using particles as a measurement sample. The mass ratios of the same active ingredient and binder as those contained in the measurement sample were 25:75, 50:50, 75:25, 92.5:7.5, 95:5, and 97.5: 2.5 and mixed to prepare 6 types of mixtures, for each mixture, the absorbance is measured using a Fourier transform infrared spectrophotometer (JASCO), the active ingredient and the binder to each A calibration curve was constructed from absorbance ratios in characteristic absorption bands. Further, the mass ratio of the same filler component and binder as the filler component and binder contained in the measurement sample was changed to 25:75, 50:50, 75:25, 92.5:7.5, 95:5, 97. Mix by changing to 5: 2.5, prepare 6 types of mixtures, measure the absorbance of each mixture using a Fourier transform infrared spectrophotometer (JASCO), and the filler component and binder. A calibration curve was created from the absorbance ratios in the absorption bands characteristic of each. For example, absorption bands of 1650 cm ⁻¹ , 3333 cm ⁻¹ and 2880 cm ⁻¹ were selected for acetaminophen, lactose monohydrate and polyethylene oxide, respectively, to prepare a calibration curve. Next, the absorbance is measured using a Fourier transform infrared spectrophotometer (JASCO) for the particles that are the measurement sample, and the measured absorbance is substituted into the function related to the calibration curve, thereby obtaining the active ingredient and The ratio of binder and the ratio of filler to binder were calculated, respectively, to calculate the ratio of binder to active ingredient, filler and binder. This existence ratio was defined as the particle coverage.

(When the filler is an inorganic compound, or a mixture of an inorganic compound and an organic compound)
When the filler is an inorganic compound, or when an inorganic compound and an organic compound are mixed, the coverage was measured by a method combining the ATR method and EDX using particles as a measurement sample. First, when the inorganic compound is included in the filler component of the particles, the coverage rate is determined using an energy dispersive X-ray spectrometer (EDS) mounted on a scanning electron microscope (JEOL Ltd., JSM-IT200LA). was calculated by quantifying the Specifically, the mass ratio of the same inorganic compound, active ingredient and binder as the inorganic compound, active ingredient and binder contained in the measurement sample is 22.5:70:7.5, 82.5:10:7. .5, 91.5: 1: 7.5 is changed and mixed to prepare three kinds of mixtures, the characteristic X-ray intensity is measured for each mixture using EDS, and A calibration curve was created from the characteristic X-ray intensities of the elements. For example, when the inorganic compound was sodium chloride, the characteristic X-ray intensities of sodium and chlorine were measured, and a calibration curve was created from the sum of the characteristic X-ray intensities of sodium and chlorine. Next, the characteristic X-ray intensity of the particles, which are the measurement samples, is measured using EDS, and the measured characteristic X-ray intensity of the inorganic compound is substituted into the function related to the calibration curve, thereby obtaining the The existence ratio of the inorganic compound that is included was calculated. The abundance ratio of the binder was calculated from the ratio of the abundance ratio of the inorganic compound to the abundance ratio of the active ingredient and the binder calculated by the ATR method. This existence ratio was defined as the coverage. It should be noted that the "ratio of active ingredient and binder calculated by the ATR method" is the same method as described in the above "When the filler is an organic compound" (however, no filler is used), and the active ingredient and The ratio of binder to binder was calculated.

<Granulation>
The granulation property was judged by visual observation. Specifically, the pharmaceutical composition obtained in each example was visually observed, and excessive granulation was observed (that is, a lumpy substance that was difficult to pulverize), and powder as it was It was judged that granulation was not possible for those with , and it was judged that granulation was possible for the others. When it was determined that granulation was possible, it was rated as "O", and when it was determined that granulation was impossible, it was rated as "x".

Table 1 shows the manufacturing conditions (blending ratio of filler, active ingredient and binder and the temperature of each heating zone) of the pharmaceutical composition produced in each example and comparative example, and also shows the granulation of the pharmaceutical composition. Figure 3 shows the evaluation results of the properties and particle coverage and the compressive strength of the tablets obtained from the pharmaceutical composition.

From Table 1, the filler and the active ingredient are contained in a ratio of 80% by mass or more and 95% by mass or less with respect to the total mass of the filler, the active ingredient, and the binder, and the content of the filler is the filler, the active ingredient, and the active ingredient. By using a pharmaceutical composition containing particles in which the component, the binder is 1 to 94% by mass with respect to the total mass of the binder, and the binder has a coverage of 20% or more on the particle surface, the compressive strength is improved. It has been found that excellent (ie with high hardness) formulations can be obtained.

Claims

A pharmaceutical composition comprising particles comprising a filler, an active ingredient and a binder,
The particles contain the filler and the active ingredient at a ratio of 80% by mass or more and 95% by mass or less with respect to the total mass of the filler, the active ingredient and the binder, and the content of the filler is 1 to 94% by weight relative to the total weight of the filler, the active ingredient, and the binder;
A composition for pharmaceutical preparation, wherein the coating rate of the binder on the particle surface is 20% or more.
2. A pharmaceutical composition according to claim 1, wherein said binder is a water-soluble polymer.
The binder is selected from the group consisting of polyethylene oxide, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polymethacrylate, copolymers of N-vinylpyrrolidone and vinyl acetate, and copolymers of N-vinylcaprolactam, vinyl acetate and ethylene glycol. The pharmaceutical composition according to claim 1, which is at least one selected.
2. The pharmaceutical composition according to claim 1, wherein the binder has a weight average molecular weight of 1000000 g/mol or less.
2. The pharmaceutical composition according to claim 1, wherein the binder is polyethylene oxide having a weight average molecular weight of 50000 g/mol or more and 1000000 g/mol or less.
A formulation comprising a pharmaceutical composition according to any one of claims 1-5.
A method for producing a pharmaceutical composition according to any one of claims 1 to 5,
A step 1 of kneading and granulating a mixture containing a filler, an active ingredient and a binder in a barrel by a twin-screw extrusion method,
The temperature in the barrel is 140° C. or less,
The weight average molecular weight of the binder is 1000000 g/mol or less,
The mixture contains the filler and the active ingredient in a ratio of 80% by mass or more and 95% by mass or less with respect to the total mass of the filler, the active ingredient and the binder,
A method for producing a pharmaceutical composition, wherein the content of the filler is 1 to 94.0% by mass with respect to the total mass of the filler, the active ingredient and the binder.