JP7627568B2 - Tablets containing oseltamivir and method for producing the same - Google Patents

Description

The present invention relates to a tablet containing oseltamivir or a pharma- ceutically acceptable salt or solvate thereof as an active ingredient, and a method for producing the tablet. The present invention relates to a method for suppressing the occurrence of binding during compression molding.

Oseltamivir is a compound represented by the following formula (I), and its chemical name is (-)-(3R, 4R, 5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)cyclohex-1-ene-1-carboxylic acid ethyl ester. Oseltamivir selectively inhibits neuraminidase of human influenza A and B viruses, inhibiting the release of newly formed viruses from infected cells, thereby suppressing the proliferation of the viruses. Currently, oseltamivir preparations on the market are capsules, and oseltamivir tablets are not commercially available, but there are several documents that describe tablets containing oseltamivir. For example, Patent Document 1 describes the manufacture of an orally disintegrating tablet containing oseltamivir by mixing pellets containing oseltamivir and starch with a tablet additive containing magnesium stearate, and compressing and molding the resulting mixed powder.

US Patent Application Publication No. 2016/0120802

The orally disintegrating tablet described in Patent Document 1 has a low oseltamivir content of about 10% by mass per tablet. The inventors therefore attempted to manufacture tablets with a higher oseltamivir content per tablet using common tablet additives, but found that binding, a type of tableting problem, occurred during compression molding. The present invention aims to provide an oseltamivir-containing tablet having a composition that suppresses the occurrence of binding.

The present inventors discovered that the occurrence of binding during compression molding can be suppressed by producing tablets using sodium stearyl fumarate as a lubricant, and completed the present invention. Therefore, the present invention provides a tablet that contains sodium stearyl fumarate as a lubricant and oseltamivir or a pharma- ceutically acceptable salt or solvate thereof as an active ingredient, and in which the content of the active ingredient is 60% by mass or more and 90% by mass or less of the total weight of the tablet.

The present invention provides a method for producing tablets that contain oseltamivir or a pharma- ceutically acceptable salt or solvate thereof as an active ingredient in an amount of 60% by mass to 90% by mass of the total mass of the tablet, the method comprising the steps of obtaining a granulated product containing the active ingredient, mixing the granulated product with sodium stearyl fumarate as a lubricant to obtain a mixture for tableting, and compressing the mixture for tableting to obtain tablets.

The present invention provides a method for suppressing the occurrence of binding during compression molding by using sodium stearyl fumarate as a lubricant in the production of tablets containing oseltamivir or a pharma- ceutically acceptable salt or solvate thereof as an active ingredient in an amount of 60% to 90% by mass of the total mass of the tablet.

The present invention provides a tablet containing oseltamivir or a pharma- ceutically acceptable salt or solvate thereof as an active ingredient, in which the occurrence of binding is suppressed, and a method for producing the tablet.

1 is a photograph showing the side view of a tablet using sodium stearyl fumarate as a lubricant. 1 is a photograph showing the side view of a tablet using sodium stearyl fumarate as a lubricant. This is a photograph showing the side of a tablet that uses magnesium stearate (common) as a lubricant. This is a photograph showing the side of a tablet that uses magnesium stearate (common) as a lubricant. 1 is a photograph showing the side view of a tablet using magnesium stearate (light) as a lubricant. 1 is a photograph showing the side view of a tablet using magnesium stearate (light) as a lubricant. 1 is a photograph showing the side of a tablet using calcium stearate as a lubricant. 1 is a photograph showing the side of a tablet using calcium stearate as a lubricant.

The tablet of this embodiment contains oseltamivir or a pharma- ceutically acceptable salt thereof, or a solvate thereof, as an active ingredient. Oseltamivir or a pharma- ceutically acceptable salt thereof refers to a salt formed from the compound represented by the above formula (I) and an organic or inorganic acid, which is acceptable for administration to mammals, including humans. Examples of such pharma- ceutically acceptable salts include phosphates, hydrochlorides, sulfates, acetates, and the like. Among these, oseltamivir phosphate is preferred.

A pharma- ceutically acceptable solvate of oseltamivir refers to a solid molecule formed from the compound represented by formula (I) above or a pharma- ceutically acceptable salt thereof and a solvent that is acceptable for administration to mammals, including humans. Examples of such solvents include water, acetic acid, and ethanol.

Hereinafter, the term "oseltamivir" includes the compound represented by the above formula (I), its pharma- ceutically acceptable salts, and solvates thereof, unless otherwise specified. The form of oseltamivir is not particularly limited, and it may be in any form, such as powder, crystal, or the like.
The particle size of oseltamivir is not particularly limited, but for example, the particle size (D ₅₀ ) of oseltamivir powder is preferably 5 μm or more and 120 μm or less, more preferably 15 μm or more and 110 μm or less. In this specification, this D ₅₀ is based on the volume-based particle size distribution measured using a laser diffraction/scattering type particle size distribution measuring device. Examples of laser diffraction/scattering type particle size distribution measuring devices include "Aerotrack LDSA-SPR" by Microtrac-Bell Co., Ltd. and "Mastersizer 3000" by Malvern Panalytical Co., Ltd.

In this embodiment, the content of oseltamivir in the tablet is 60% by mass or more and 90% by mass or less of the total mass of the tablet. The lower limit of the content of oseltamivir in the tablet is, for example, 60% by mass, 65% by mass, or 70% by mass. The upper limit of the content of oseltamivir in the tablet is, for example, 90% by mass, 85% by mass, or 80% by mass.

The tablet of this embodiment contains sodium stearyl fumarate as a lubricant. In this embodiment, by producing the tablet using sodium stearyl fumarate as a lubricant, the occurrence of binding during tablet production can be suppressed. Binding refers to the phenomenon in which scratches occur on the side of a tablet when the tablet is compressed.

The particle size of the sodium stearyl fumarate used is not particularly limited, but for example, the particle size ( _D50 ) of the sodium stearyl fumarate powder is preferably 0.3 μm or more and 10 μm or less, more preferably 0.5 μm or more and 7 μm or less, and even more preferably 1 μm or more and 4 μm or less.
The content of sodium stearyl fumarate in the tablet is preferably 0.9% by mass or more and 2.0% by mass or less of the total mass of the tablet. The upper limit of the content of sodium stearyl fumarate in the tablet is, for example, 2.0% by mass, 1.9% by mass, 1.8% by mass, 1.7% by mass, or 1.6% by mass. The lower limit of the content of sodium stearyl fumarate in the tablet is, for example, 0.9% by mass, 1.0% by mass, 1.1% by mass, 1.2% by mass, or 1.3% by mass.

In the tablet of this embodiment, the mass ratio of sodium stearyl fumarate to oseltamivir is, for example, 0.010 or more and 0.030 or less. The lower limit of the mass ratio of sodium stearyl fumarate to oseltamivir in the tablet is, for example, 0.010, 0.011, 0.012, 0.013, 0.014, or 0.015. The upper limit of the mass ratio of sodium stearyl fumarate to oseltamivir in the tablet is, for example, 0.030, 0.029, 0.028, 0.027, 0.026, 0.025, 0.024, 0.023, 0.022, 0.021, or 0.020.

In a preferred embodiment, the tablet is substantially free of lubricants other than sodium stearyl fumarate. Here, "substantially free" means that the tablet contains only small amounts of lubricants other than sodium stearyl fumarate, if any, and that lubricants other than sodium stearyl fumarate are not actively added. Examples of cases in which a small amount of lubricant other than sodium stearyl fumarate is contained include cases in which it is mixed in as an impurity, or cases in which a small amount is generated as a result of some kind of chemical reaction or decomposition of a contained component, etc.

In another embodiment, the tablet may further contain a pharma- ceutically acceptable lubricant other than sodium stearyl fumarate, if necessary. Examples of such lubricants include talc, light anhydrous silicic acid, magnesium stearate, and calcium stearate. The lubricant other than sodium stearyl fumarate may be one type, or two or more types may be combined. In this embodiment, the content of sodium stearyl fumarate in the tablet and the mass ratio of sodium stearyl fumarate to oseltamivir are as described above. The upper limit of the content of all lubricants including sodium stearyl fumarate is preferably, for example, 2.0% by mass or less. In addition, the upper limit of the mass ratio of all lubricants including sodium stearyl fumarate to oseltamivir in the tablet is preferably, for example, 0.030 or less.

In this embodiment, the tablet may further include a tablet additive. The tablet additive refers to a pharma- ceutical additive that is used in the manufacture of tablets and is a pharma- ceutical additive. Such tablet additives can be appropriately selected from pharma- ceutical acceptable excipients, disintegrants, binders, sweeteners, colorants, and the like.

Examples of pharma- ceutically acceptable excipients include starches, celluloses, sugars, and sugar alcohols. Examples of starches include partially pregelatinized starch and corn starch. Examples of celluloses include crystalline cellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, and low-substituted hydroxypropyl cellulose. Examples of sugars include lactose (also called lactose hydrate) and sucrose. Examples of sugar alcohols include D-sorbitol and D-mannitol. One type of excipient may be used, or two or more types may be combined.

Examples of pharma- ceutically acceptable binders include hydroxypropyl cellulose, hypromellose, ethyl cellulose, polyvinylpyrrolidone, etc. Among these, it is preferable to use hydroxypropyl cellulose. The binder may be one type or a combination of two or more types.
When hydroxypropyl cellulose is used as a binder, the viscosity of the hydroxypropyl cellulose is not particularly limited, but is preferably 2 mPa·s or more and 10 mPa·s or less. Here, the viscosity of hydroxypropyl cellulose in this specification refers to the value measured by the viscosity measurement method described in the Japanese Pharmacopoeia, in a 2% by mass aqueous solution of hydroxypropyl cellulose at 20°C. For example, the hydroxypropyl cellulose may have a viscosity of 2 mPa·s or more and 2.9 mPa·s or less, 3 mPa·s or more and 5.9 mPa·s or less, or 6 mPa·s or more and 10 mPa·s or less.

Examples of pharma- ceutically acceptable sweeteners include acesulfame potassium, sucralose, aspartame, and sodium saccharin. A single type of sweetener may be used, or two or more types may be combined.

Examples of pharma- ceutically acceptable coloring agents include ferric oxide and yellow ferric oxide. A single coloring agent may be used, or two or more types may be combined.

Pharmaceutically acceptable disintegrants include crospovidone, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, corn starch, etc. One type of disintegrant may be used, or two or more types may be combined.

The tablet may be further coated as necessary. A known coating method can be used for coating. For example, pan coating method, fluidized bed coating method, etc. can be used. By coating the tablet, the bitterness of oseltamivir can be suppressed. Examples of coating agents include hypromellose, ethyl cellulose, talc, titanium oxide, silicic acid, hydroxypropyl cellulose, polyvinylpyrrolidone, aminoalkyl methacrylate copolymer, polyvinyl alcohol, polyvinyl alcohol diethylaminoacetate, polyvinyl alcohol acetate phthalate, cellulose acetate phthalate, hypromellose phthalate, methacrylic acid copolymer, copolymer of methyl methacrylate, butyl methacrylate, and dimethylaminoethyl methacrylate. The coating agent may be one type or two or more types in combination.
When hypromellose is used as a coating agent, the viscosity of the hypromellose is not particularly limited, but is preferably 3 mPa·s or more and 10 mPa·s or less. Here, the viscosity of hypromellose in this specification refers to the value obtained by measuring the viscosity of a 2% by mass aqueous solution of hypromellose at 20°C based on the viscosity measurement method described in the Japanese Pharmacopoeia. As the hypromellose, for example, one having a viscosity of 4.8 mPa·s or more and 7.2 mPa·s or less may be used.

The tablets may be packaged, as necessary, in PTP packaging, bottles, aluminum packaging, or the like.
Examples of materials for PTP packaging include resins such as polyvinyl chloride, polypropylene, polyvinylidene chloride, polychlorotrifluoroethylene, polyethylene, polystyrene, and polycarbonate, and metals such as aluminum. These materials may be used alone or in combination. Examples of combinations include laminating polyvinyl chloride and polyvinylidene chloride, and laminating polyvinyl chloride and polychlorotrifluoroethylene. The above resins are molded by a known method into a resin sheet, and tablets are placed in the molded pockets and covered with aluminum foil to complete packaging.
The PTP package containing the tablet may be further packaged in an aluminum pillow. This aluminum pillow may further contain a desiccant. Examples of the desiccant include calcium chloride, calcium oxide, magnesium oxide, silica gel, and zeolite.

One embodiment of the present invention is a method for producing a tablet containing oseltamivir as the active ingredient in an amount of 60% by mass to 90% by mass of the total mass of the tablet. This production method is described below.

First, oseltamivir and tablet additives excluding lubricants are mixed to obtain a mixture for granulation. Mixing of oseltamivir and tablet additives excluding lubricants can be performed by a method known in the art. When mixing is performed manually, for example, bag mixing may be performed in which oseltamivir and excipients are placed in a suitable bag and stirred. When mixing is performed mechanically, a mixer known in the art may be used. The mixer may be either a rotary mixer or a fixed mixer. A rotary mixer is a machine that mixes powder contained in a container by rotating the container itself. A fixed mixer is a machine that mixes powder contained in a container by rotating agitation blades, screws, etc. provided in the container. Examples of mixers include V-type mixers, double cone mixers, ribbon mixers, and cone screw mixers. Alternatively, the mixture may be introduced into an apparatus that can also perform the granulation process described below, such as an agitation granulator, and mixed therein. The amount of oseltamivir and tablet additives to be mixed can be set appropriately depending on the mixer used.

The tablet additives can be appropriately selected from those mentioned above. Among the tablet additives, it is preferable to use an excipient and/or a binder, and it is preferable to use D-mannitol as the excipient and hydroxypropyl cellulose as the binder.
Oseltamivir and/or tablet additives may be crushed in advance by an impact crusher or the like before mixing. The impact crusher is not particularly limited, and any device known in the art can be used. Examples of such devices include a pin mill and a hammer mill.

Next, the mixture for granulation is put into a granulator and granulated to obtain a granulated product containing oseltamivir as an active ingredient. The granulator is not particularly limited as long as it does not affect the physical properties of oseltamivir. For example, an agitation granulator, a fluidized bed granulator, a dry granulator, etc. can be used as the granulator. The device may also have a drying function. The mixture for granulation or the granulated product may be classified by passing it through a sieve having a specific mesh. By passing it through a sieve, the particle size of the mixture for granulation or the granulated product can be adjusted to an appropriate size.
The moisture value of the obtained granules is not particularly limited, but is preferably 3% by mass or less, more preferably 2.5% by mass or less, more preferably 2% by mass or less, more preferably 1.5% by mass or less, and more preferably 1.0% by mass or less. The moisture value in this specification is a value measured based on the loss on drying test method. The moisture value in the present invention is a value measured based on the loss on drying test method.

The obtained granules are mixed with sodium stearyl fumarate as a lubricant to obtain a mixture for tableting. The above-mentioned mixer can be used to mix the granules with sodium stearyl fumarate. The amount of the granules and sodium stearyl fumarate to be mixed can be appropriately set depending on the mixer used.

The obtained mixture for tableting can be compressed and molded using a tablet press to obtain tablets (plain tablets). "Plain tablets" refer to tablets that have not been coated. A publicly known tablet press can be used for compression molding. For example, a rotary tablet press can be used as a publicly known tablet press.

The obtained tablets may be further coated as necessary. As the coating method, a known coating method can be used. For example, a pan coating method, a fluidized bed coating method, etc. can be used. The coating agent used can be appropriately selected from those described above. The coating agent can be appropriately prepared to form a film coating liquid. For example, the film coating liquid can be prepared by dispersing hypumellose, hydroxypropyl cellulose, talc, and titanium oxide in purified water.

The mass of the tablets produced is not particularly limited, but it is preferable that the tablets contain at least 75 mg of the compound represented by formula (I). The mass of the tablets is, for example, 50 mg or more and 500 mg or less per tablet, preferably 100 mg or more and 400 mg or less, more preferably 100 mg or more and 300 mg or less, and more preferably 100 mg or more and 200 mg or less.

By manufacturing tablets using sodium stearyl fumarate as a lubricant, tablets with excellent hardness can be obtained. The higher the tablet hardness, the more likely it is that chipping during manufacturing will be prevented, so this is preferable. The tablet hardness is preferably 75N or more, more preferably 80N or more, even more preferably 85N or more, and even more preferably 90N or more.

The tableting pressure when producing tablets is not particularly limited and can be set appropriately depending on the composition and weight of the tablet. The tableting pressure can be set, for example, to 3 kN or more and 12 kN or less, and is preferably 4 kN or more and 10 kN or less.

The moisture content of the obtained tablets is not particularly limited and will vary depending on the tablet management conditions, but is preferably 3% by mass or less, more preferably 2.5% by mass or less, more preferably 2% by mass or less, more preferably 1.5% by mass or less, more preferably 1.0% by mass or less, and more preferably 0.8% by mass or less.

One embodiment of the present invention is a method for suppressing the occurrence of binding during compression molding. By using sodium stearyl fumarate as a lubricant and producing a tablet containing oseltamivir as an active ingredient in an amount of 60% by mass to 90% by mass of the total mass of the tablet, the occurrence of binding during compression molding can be suppressed. Details of tablet production using this method are the same as those described above for the tablet production method of this embodiment.

The present invention will be explained in more detail below with reference to examples and comparative examples, but the present invention is not limited to these in any way.

(Study on the physical properties of tablets with different lubricants)
Here, we investigated the binding and physical properties of tablets produced when tablets were produced using oseltamivir and sodium stearyl fumarate as a lubricant (Examples 1 and 2), when tablets were produced using magnesium stearate instead of sodium stearyl fumarate as a lubricant (Comparative Examples 1 to 4), and when tablets were produced using calcium stearate instead of sodium stearyl fumarate as a lubricant (Comparative Examples 5 and 6).

Preparation of granules containing oseltamivir as an active ingredient Oseltamivir phosphate was put into an impact crusher to crush the oseltamivir phosphate. The particle size (D ₅₀ ) of the crushed oseltamivir phosphate was measured by Mastersizer 3000, and D ₅₀ was 22 μm. The crushed oseltamivir phosphate and D-mannitol were put into a stirring granulator and mixed. After mixing, purified water was sprayed to granulate. The granulated powder was dried and sized to obtain a granule containing oseltamivir as an active ingredient. The moisture content of the granule was 0.06% by mass.

- Manufacture of tablets of Examples 1 and 2 The following Table 1 shows the formulations (amounts of ingredients per tablet) of the tablets of Examples 1 and 2. The tablets were manufactured as follows.
The granules prepared in the above-mentioned preparation of the granules and sodium stearyl fumarate were mixed in a bag to obtain a mixture for tableting. The obtained mixture for tableting was compressed with a rotary tableting machine at a tableting pressure of 7 kN to obtain tablets of Example 1 and Example 2. The obtained tablets were observed to confirm whether binding occurred.

The thickness, hardness and disintegration time of the obtained tablets were measured. Tablet thickness refers to the length from the apex of the protuberance on the upper surface of the manufactured tablet to the apex of the protuberance on the lower surface, and was measured using a dial thickness gauge (TECLOCK). Hardness was measured using a tablet hardness tester (ERWAKA). Disintegration time was measured according to the disintegration test method of the Japanese Pharmacopoeia.

Manufacture of tablets in comparative examples Table 1 below shows the formulations (amount of ingredients per tablet) of the tablets in comparative examples 1 to 6. Each tablet contains 75 mg of oseltamivir represented by formula (I). In comparative examples 1 and 2, magnesium stearate (general: Taihei Chemical Industry Co., Ltd.) was used as a lubricant instead of sodium stearyl fumarate, in comparative examples 3 and 4, magnesium stearate (light: Taihei Chemical Industry Co., Ltd.) was used as a lubricant instead of sodium stearyl fumarate, and in comparative examples 5 and 6, calcium stearate was used as a lubricant instead of sodium stearyl fumarate. The two types of magnesium stearate used in the comparative examples have different particle sizes, with the light magnesium stearate having a smaller particle size than the general magnesium stearate. The tablet thickness, hardness and disintegration time of each tablet obtained were measured in the same manner as in examples 1 and 2.

The measurement results for each tablet of the Examples and Comparative Examples are shown in Table 2 below. Examples of observations of each tablet are shown in Figures 1A to 4B. Figure 1A shows the tablet of Example 1, Figure 1B shows the tablet of Example 2, Figure 2A shows the tablet of Comparative Example 1, Figure 2B shows the tablet of Comparative Example 2, Figure 3A shows the tablet of Comparative Example 3, Figure 3B shows the tablet of Comparative Example 4, Figure 4A shows the tablet of Comparative Example 5, and Figure 4B shows the tablet of Comparative Example 6. In the binding column in Table 2, ◯ indicates that binding hardly occurred in the tablets measured, and × indicates that binding frequently occurred in the tablets measured. The tablet thickness of each tablet was all 3.3 mm.

The results in Table 2 show that tablets manufactured using sodium stearyl fumarate as a lubricant hardly experienced any binding, indicating that the use of sodium stearyl fumarate as a lubricant reduces the occurrence of binding. It was also shown that while the use of magnesium stearate as a lubricant reduced hardness, tablets manufactured using sodium stearyl fumarate as a lubricant had high hardness, indicating that tablets manufactured using sodium stearyl fumarate as a lubricant have excellent physical properties as tablets.

(Prescription example)
Examples of tablet formulations and physical properties of the produced tablets are shown in the following Tables 3 and 4. Granulation and tableting can be carried out, for example, in the same manner as in the preparation of granules and production of tablets described above, or they can be produced as follows.

1) Put oseltamivir phosphate into an impact mill and pulverize to obtain pulverized oseltamivir phosphate (the pulverized oseltamivir phosphate in Formulation Example 1 below has a _D50 of 22 μm. Oseltamivir phosphate may be used without being pulverized. In Formulation Examples 2 to 4 below, unpulverized oseltamivir phosphate is used, and the _D50 is 90 μm).
2) The crushed product (or uncrushed oseltamivir phosphate) from 1), D-mannitol and hydroxypropyl cellulose were added to a stirring granulator and mixed. After mixing, purified water was sprayed to obtain a granulated powder containing oseltamivir phosphate as an active ingredient.
3) The granulated powder of 2) is dried and sized to obtain a granulated material containing oseltamivir phosphate as an active ingredient.
4) The granules of 3) and sodium stearyl fumarate are mixed using a diffusion mixer (hydroxypropyl cellulose may be added to the granules and mixed before mixing with sodium stearyl fumarate) to obtain a mixture for tableting containing oseltamivir phosphate as an active ingredient.
5) The mixture for tableting in 4) is tableted using a rotary tableting machine to obtain tablets (plain tablets) containing oseltamivir phosphate as an active ingredient.

The tablet diameter was measured using a dial thickness gauge, similar to the tablet thickness. Film coating can be carried out, for example, by the following procedure.

1) Hypromellose and hydroxypropyl cellulose are dissolved in purified water. Talc is added to the solution and dispersed to obtain Dispersion I.
2) Titanium oxide is dispersed in purified water to obtain dispersion II.
3) Dispersion I and Dispersion II are mixed to obtain a film coating liquid.
4) Tablets containing oseltamivir as the active ingredient (the tablets may be placed in a thermo-hygrostat to adjust the humidity before coating) are placed in a coating pan machine, coated with the film coating solution, and then dried to obtain film-coated tablets.

Claims (1)

A method for suppressing the occurrence of binding during compression molding by using sodium stearyl fumarate as a lubricant in the manufacture of tablets containing oseltamivir or a pharma- ceutically acceptable salt or solvate thereof as an active ingredient in an amount of 60% to 90% by mass of the total mass of the tablet.