WO2016144023A1 - Tablet containing tenofovir disoproxil free base and preparation method therefor - Google Patents

Abstract

Provided are a tablet free of a metal-containing lubricant and a preparation method therefor, the tablet containing: a tenofovir disoproxil free base as a pharmaceutically active ingredient; and one or more metal-free lubricants selected from the group consisting of glyceryl behenate, hydrogenated castor oil, a sucrose fatty acid ester, hardened vegetable oil, stearic acid, and polyethylene glycol.

Description

Tablets containing tenofovir disoproxyl free base and preparation method thereof

The present invention relates to a tablet comprising tenofovir disoproxyl free base as a pharmaceutically active ingredient. More specifically, the present invention provides a pharmaceutical composition comprising tenofovir disoproxyl free base; And a free of metal-containing lubricant, comprising a free of metal-containing lubricant.

Tenofovir disoproxyl is a prodrug that improves physiological oral activity by attaching physiologically hydrolysable ester bonds to phosphinyl-methoxy-propyl-adenine (PMPA or tenofovir). Tenofovir disoproxyl is a neutride reverse transcriptase inhibitor having an antiviral effect and is widely used as a drug for treating AIDS and hepatitis B with a viridra product name.

<Formula 1>

Tenofovir disoproxyl has an ester bond, which tends to hydrolyze the ester bond during storage, resulting in a loss of the protective masking group in ester form, resulting in a reduced biomass. There is a problem of utilization and low oral activity. In particular, tenofovir disoproxyl is susceptible to chemical degradation by moisture, which results in oral inactivation of mono-POC PMPA, dimers, mono-POC dimers, mixed dimers, IPC-mixed There is a problem that impurities such as trimmers (IPC-mixed trimer) are caused.

Mono-POC PMPA

<Dimer>

In order to improve the stability of tenofovir disoproxyl, U.S. Pat.No. 5,935,946 discloses a crystalline form consisting of tenofovir disoproxyl fumarate complexes each comprising a portion of tenofovir disoproxyl and a portion of fumaric acid. have. In addition, U. S. Patent No. 6,635, 278 discloses the addition of an alkaline excipient such as magnesium or calcium carbonate to a tablet composition comprising crystalline adefovir dipoxyl and optionally containing L-carnitine-L-tartrate to remove impurities such as monoesters. It has been disclosed to reduce the formation. In addition, Korean Patent Publication No. 10-2013-0126951 discloses a composition having storage stability by making and formulating a molecular dispersion of adefovir difficile in copovidone as a polymer. In addition, various new salts have been disclosed for improving the stability of tenofovir disoproxyl (Korean Patent Registration No. 10-1458330, 10-1439255, Korean Patent Publication No. 10-2015-0005818, etc.).

The inventors of the present invention have conducted various studies to develop a pharmaceutical composition having a tenofovir disoproxyl free base, which minimizes the formation of a flexible substance (especially Mono-POC PMPA) during formulation and also has an excellent storage stability. It was. The inventors have found that glidants used in the formulation process, in particular metal-containing glidants such as magnesium stearate, promote the formation of analogues of tenofovir disoproxyl. In addition, the inventors have found that when formulated using antioxidants, tablets containing tenofovir disoproxyl freebases with good storage stability can be prepared.

Accordingly, it is an object of the present invention to provide a tablet containing tenofovir disoproxyl free base, which contains a metal-free lubricant and / or an antioxidant.

In addition, an object of the present invention is to provide a method for producing a tablet containing the tenofovir disoproxyl free base.

According to one aspect of the present invention, there is provided a tenofovir disoproxyl free base as a pharmaceutically active ingredient; And a metal-free glidant selected from the group consisting of glyceryl bicarbonate, hardened castor oil, sucrose fatty acid ester, vegetable hardened oil, stearic acid, and polyethylene glycol. of metal-containing lubricant).

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising tenofovir disoproxyl free base; Metal-free lubricants selected from the group consisting of glyceryl bicarbonate, hardened castor oil, sucrose fatty acid ester, vegetable hardened oil, stearic acid, and polyethylene glycol; And tableting a mixture comprising a pharmaceutically acceptable excipient and a disintegrant.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising (a) tenofovir disoproxyl free base as a pharmaceutically active ingredient; Metal-free lubricants selected from the group consisting of glyceryl bicarbonate, hardened castor oil, sucrose fatty acid esters, vegetable hardened oils, stearic acid, and polyethylene glycol; Forming a dry granule with a mixture comprising a pharmaceutically acceptable excipient and a disintegrant, and (b) the granule obtained in step (a); Metal-free lubricants selected from the group consisting of glyceryl bicarbonate, hardened castor oil, sucrose fatty acid ester, vegetable hardened oil, stearic acid, and polyethylene glycol; And tableting a mixture of a pharmaceutically acceptable disintegrant. There is provided a process for the preparation of a tablet containing tenofovir disoproxyl free base.

It has been found by the present invention that metal-containing glidants, such as magnesium stearate, promote the formation of the flexible material of tenofovir disoproxyl, and according to the present invention metal-free gliders such as fatty acids, fatty acid derivatives, waxes, etc. When formulated using an agent, it is possible to minimize the formation of analogs (particularly Mono-POC PMPA) of tablets containing tenofovir disoproxyl freebase. In addition, when formulated using an antioxidant according to the present invention, it is possible to prepare tablets containing tenofovir disopoxyl free bases having good storage stability.

The present invention provides a pharmaceutically active ingredient, tenofovir disoproxyl free base; And a metal-free glidant selected from the group consisting of glyceryl bicarbonate, hardened castor oil, sucrose fatty acid ester, vegetable hardened oil, stearic acid, and polyethylene glycol. of metal-containing lubricants.

It has been found by the present invention that the metal-containing glidants, such as magnesium stearate, promote the formation of analogues of tenofovir disoproxyl by the present invention. That is, it has been found that tenofovir disophyxyl freebase is decomposed into a mono-ester form by water, in which a lubricant containing metal ions acts as a hydrolysis catalyst. Therefore, according to the present invention, when formulated with a metal-free lubricant such as fatty acids, fatty acid derivatives, waxes, etc., the flexible substance of the tablet containing tenofovir disoproxyl free base (especially Mono The production of -POC PMPA) can be minimized. The metal-free lubricant may be preferably selected from the group consisting of glyceryl behenate, hydrogenated castor oil, and hydrogenated vegetable oil. In addition, the metal-free lubricant may be present at 0.5 to 15% by weight, preferably 1.0 to 10% by weight relative to the total weight of the tablet. When the content of the metal-free lubricant is less than 0.5% by weight, the tablet may not be properly lubricated and tableting disorders such as sticking may occur. In addition, when the content of the metal-free lubricant is more than 15% by weight, disintegration of the tablet may be delayed and elution may be lowered in the body.

In addition, tenofovir disophyxyl free bases tend to react with each other in a storage state to form dimers or mixed dimers. According to the present invention, when the formulation is carried out using an antioxidant, the production of dimers or mixed dimers of tenofovir disophyxyl is suppressed, and the production of impurities such as mono-esters is also reduced, resulting in excellent storage stability. It has been found that tablets containing Norphovir disoproxyl free base can be prepared. The antioxidants are sodium bisulfite, butylated hydroxytoluene, butylated hydroxyaniline, ascorbic acid, alpha-tocopherol, ascorbic acid palmitate, sodium ascorbate, metabisulfite potassium, propyl gallate, sodium meta One or more selected from the group consisting of bisulfite, sodium thiosulfate, and coenzyme Q10. Preferably, the antioxidant may be selected from the group consisting of sodium bisulfite, sodium metabisulfite, and butylated hydroxytoluene. The antioxidant may be present at 0.1 to 20% by weight, preferably 0.5 to 5% by weight relative to the total weight of the tablet. If the content of the antioxidant is less than 0.1% by weight it may be difficult to improve the storage stability. In addition, when the content of the antioxidant exceeds 20% by weight may not be able to include other pharmaceutical excipients may be difficult to manufacture tablets.

Tablets containing tenofovir disoproxyl free base according to the present invention are pregelatinized starch, microcrystalline cellulose, lactose (e.g. monohydrate, anhydrous lactose, etc.), mannitol, glucose, maltitol, dextrin, cyclodextrin, One or more excipients selected from the group consisting of isomalt, maltodextrin, dexrate, crystalline cellulose, starch (corn starch, potato starch, etc.), sucrose, low-substituted hydroxypropylmethylcellulose, chitosan, and gelatin; And at least one disintegrant selected from the group consisting of croscarmellose sodium, crospovidone, and sodium starch glyconate. In addition, as the excipient, it is also possible to use Ludipress ^™ mixed with microcrystalline cellulose. In one embodiment, the excipient may be selected from one or more from the group consisting of pregelatinized starch, microcrystalline cellulose, lactose, and mannitol; The disintegrant may further include a disintegrant selected from the group consisting of croscarmellose sodium and crospovidone.

In addition, tablets according to the present invention may comprise at least one lubricant (or flow improving agent) selected from the group consisting of colloidal silicon dioxide and light silicic anhydride; Or a pH adjusting agent selected from the group consisting of glutamic acid, oxalic acid, citric acid, succinic acid, fumaric acid, tartaric acid, maleic acid, and malic acid. In one embodiment, the lubricant may be colloidal silicon dioxide or hard silicic acid; The pH adjusting agent may be selected from one or more from the group consisting of glutamic acid and oxalic acid. In addition, if necessary, a binder selected from the group consisting of polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropylmethylcellulose, copovidone, polyvinyl alcohol, starch, and gelatin may be further included. In addition, the tablet according to the present invention may include a conventional coating layer, such as a film coating layer, sugar coating layer.

The present invention includes a process for the preparation of tablets containing the tenofovir disoproxyl free base according to the invention described above. The production method of the present invention is preferably carried out under conditions that can all the process to avoid the instability of the tenofovir disoproxyl free base to the water as possible. That is, the manufacturing method according to the present invention is preferably performed without using water or a solvent at a relative humidity of 60% or less.

In one embodiment, the present invention includes a manufacturing method according to a direct tableting method. In other words, the present invention provides a pharmaceutically active ingredient, tenofovir disoproxyl free base; Metal-free lubricants selected from the group consisting of glyceryl bicarbonate, hardened castor oil, sucrose fatty acid ester, vegetable hardened oil, stearic acid, and polyethylene glycol; And tableting a mixture comprising a pharmaceutically acceptable excipient and a disintegrant.

In another embodiment, the present invention includes a process according to the dry granulation method. That is, the present invention provides a pharmaceutical composition comprising: (a) tenofovir disoproxyl free base as a pharmaceutically active ingredient; Metal-free lubricants selected from the group consisting of glyceryl bicarbonate, hardened castor oil, sucrose fatty acid esters, vegetable hardened oils, stearic acid, and polyethylene glycol; And forming dry granules with a mixture comprising a pharmaceutically acceptable excipient and a disintegrant, (b) the granules obtained in step (a); Metal-free lubricants selected from the group consisting of glyceryl bicarbonate, hardened castor oil, sucrose fatty acid ester, vegetable hardened oil, stearic acid, and polyethylene glycol; And tableting a mixture of pharmaceutically acceptable disintegrants. The method provides a method for preparing a tablet containing tenofovir disoproxyl free base.

In the production method of the present invention, the metal-free lubricant may preferably be selected from the group consisting of glyceryl bicarbonate, cured castor oil, and vegetable cured oil. In addition, the metal-free lubricant may be used in an amount of 0.5 to 15% by weight, preferably 1.0 to 10% by weight, based on the total weight of the tablet.

The mixture in the production method according to the direct tableting method; Or the mixture of step (a) in the preparation method according to the dry granulation compression method is sodium bisulfite, butylated hydroxytoluene, butylated hydroxyaniline, ascorbic acid, alpha-tocopherol, ascorbic acid palmitate, And at least one antioxidant selected from the group consisting of sodium ascorbate, potassium metabisulfite, propyl gallate, sodium metabisulfite, sodium thiosulfate, and coenzyme Q10. Preferably, the antioxidant may be selected from the group consisting of sodium bisulfite, sodium metabisulfite, and butylated hydroxytoluene. The antioxidant may be used in an amount of 0.1 to 20% by weight, preferably 0.5 to 5% by weight based on the total weight of the tablet.

Of the mixtures in the preparation method according to the direct tableting method, the excipients are pregelatinized starch, microcrystalline cellulose, lactose (for example monohydrate, anhydrous lactose, etc.), mannitol, glucose, maltitol, dextrin, cyclodextrin At least one selected from the group consisting of isomalt, maltodextrin, dexrate, crystalline cellulose, starch (corn starch, potato starch, etc.), sucrose, low-substituted hydroxypropylmethylcellulose, chitosan, and gelatin; The disintegrant may be selected from the group consisting of croscarmellose sodium, crospovidone, and sodium starch glyconate. The mixture may also comprise one or more lubricants selected from the group consisting of colloidal silicon dioxide and hard silicic anhydride; Or a pH adjusting agent selected from the group consisting of glutamic acid, oxalic acid, citric acid, succinic acid, fumaric acid, tartaric acid, maleic acid, and malic acid.

In the preparation method according to the dry granulation compression method, the excipient is pregelatinized starch, microcrystalline cellulose, lactose (for example monohydrate, anhydrous lactose, etc.), mannitol, glucose, maltitol, dextrin, cyclodextrin, isomalt One or more selected from the group consisting of maltodextrin, dexrate, crystalline cellulose, starch (corn starch, potato starch, etc.), white sugar, low-substituted hydroxypropylmethylcellulose, chitosan, and gelatin; The disintegrant of step (a) and step (b) may be independently selected from the group consisting of croscarmellose sodium, crospovidone, and sodium starch glyconate. Further, the mixture of step (a) may comprise at least one lubricant selected from the group consisting of colloidal silicon dioxide and light silicic anhydride; Or a pH adjusting agent selected from the group consisting of glutamic acid, oxalic acid, citric acid, succinic acid, fumaric acid, tartaric acid, maleic acid, and malic acid.

In addition, if necessary, the production method of the present invention may further include a conventional coating layer forming process, such as a film coating layer, sugar coating layer. For example, a coating layer forming process may be performed by spraying a solution obtained by dissolving a conventional coating material in 99% or more of alcohol.

Hereinafter, the present invention will be described in more detail through Examples and Test Examples. However, these Examples and Test Examples are for illustrating the present invention, the present invention is not limited to these Examples and Test Examples.

Examples 1 to 4: Preparation of Tablets (Direct Tableting Method)

A tablet containing tenofovir disophyxyl free base was prepared according to the ingredients and contents of Table 1 below. The content in Table 1 represents the weight per unit tablet (mg) and all processes were performed under relative humidity below 50%.

Tenofovir disophyxyl freebase, excipients (pregelatinized starch, microcrystalline cellulose, lactose (apples at 200 mesh), and / or mannitol), and disintegrants (crosamelose sodium or crospovidone) were mixed. The resulting mixture is mixed with a lubricant (colloidal silicon dioxide, Examples 3 and 4) or a pH adjuster (glutamic acid, Examples 1 and 4), followed by antioxidants (sodium bisulfite or butylated hydroxytoluene) and glidants ( Hardened castor oil or vegetable hardened oil). The resulting mixture was compressed into tablets using a rotary tablet press (DCM Korea Co., Model: DP-2008) to prepare a tablet containing tenofovir disophyxyl free base.

TABLE 1

Examples 5 to 10 Preparation of Tablets (Dry Granulation Compression)

A tablet containing tenofovir disophyxyl free base was prepared according to the ingredients and contents of Table 2 below. The content in Table 2 represents the weight per unit tablet (mg) and all processes were performed under relative humidity of about 43%.

Tenofovir disophyxyl freebase, excipients (pregelatinized starch, microcrystalline cellulose, lactose (apples at 200 mesh), and / or mannitol), and disintegrant (crocamellose sodium) were mixed. The resulting mixture is mixed with a lubricant (colloidal silicon dioxide, Example 5), a pH adjuster (oxalic acid, Example 7), or an antioxidant (sodium metabisulfite or sodium bisulfite, Examples 6 to 10) and then lubricated The agent (cured castor oil) was mixed. The obtained mixture was appled with a 20 mesh sieve and then passed through a compression roller rotating at a speed of 10 rpm per minute in a compressed granulator (FEUND, Model: TF-LAB0) to prepare dry granules. The granules thus obtained are sieved through an 18 mesh sieve in an oscillator, then mixed with a disintegrant (crosamelose sodium) and a lubricant (cured castor oil, vegetable hardened oil, or glyceryl bivinate), followed by a rotary tablet press (DCM Korea) , Model: DP-2008) to tablets containing tenofovir disophyxyl free base were prepared.

TABLE 2

Test Example  One: Leading substance  analysis

For tablets that do not contain antioxidants, the relationship between glidant and lead content was analyzed. That is, a tablet (Comparative Example 1) was prepared in the same manner as in Example 2 using magnesium stearate as a lubricant in the composition of Example 2 (excluding the antioxidant). In addition, a tablet (Example 11) containing vegetable hardened oil as a lubricant was prepared for comparison. Each tablet was prepared under the operating conditions of 50% or less relative humidity, and the components and contents of each tablet are shown in Table 3 below. The content in Table 3 represents the weight per unit tablet (mg).

TABLE 3

The contents of the mono-POC PMPA in the tablets of Comparative Examples 1 and 11 were analyzed, and each tablet was stored at 25 ° C./15% for 4 weeks, and then the contents of the mono-POC PMPA. Was analyzed. The content of the analog was analyzed as follows: Tenofovir disoproxyl free base standard was dissolved in acetonitrile and prepared at a concentration of 1.5 mg / mL to prepare a standard solution, and two tablets of Comparative Example 1 and Example 11 were prepared. Into a 200 mL volumetric flask was added about 120 mL of 25 mmol / L potassium phosphate solution (pH 3) and stirred until the tablets completely disintegrated. Acetonitrile was added to this solution until the mark below the flask and mixed well. The mark of this solution was matched using the potassium phosphate solution and used as a sample solution. The flexible material content was analyzed using high performance liquid chromatography under the conditions of Table 4 below, and the results are shown in Table 5.

TABLE 4

TABLE 5

Content of Mono-POC PMPA

As can be seen from the results of Table 5, the tablet using the metal-free lubricant as a lubricant according to the present invention not only has a low content of the initial softening material, but also has a significant content of the softening material even after storage for 4 weeks. No increase was observed. However, in the tablet of Comparative Example 1 using a metal-containing lubricant, a significant increase in the content of the flexible substance was observed.

Test Example  2: Assessment of the Effects of Antioxidants

Tablets containing or without antioxidant were prepared to evaluate the stability according to the antioxidant. That is, in the same manner as in Examples 5 to 10, tablets containing sodium bisulfite as the antioxidant (Formulation Example 2) and tablets containing no antioxidant (Formulation Example 1) were prepared. Components and contents of each tablet are shown in Table 6 below. The content in Table 6 represents the weight (mg) per unit tablet.

TABLE 6

The contents of the initial analogues in the tablets of Formulation Examples 1 and 2 were analyzed, and each tablet was stored under 25 ° C / 93% harsh conditions for 2 weeks, after which the analogues (Mono-POC PMPA, mono-POC Dimer, IPC) -mixed trimer) content was analyzed. The content of the flexible material was analyzed under the conditions of Test Example 1 according to the high performance liquid chromatography (HPLC) method described in the Korean Pharmacopoeia (KP). The results are shown in Table 7 below.

TABLE 7

N.D: not detected

As can be seen from the results of Table 7, the tablet containing the antioxidant according to the present invention not only has a lower content of the initial softening material, but also has a significant increase in the content of the softening material even after storage for 2 weeks in harsh conditions. Not observed.

Claims (19)

As a pharmaceutically active ingredient, tenofovir disoproxyl free base; And a metal-free lubricant comprising at least one metal-free lubricant selected from the group consisting of glyceryl bicarbonate, hardened castor oil, sucrose fatty acid ester, vegetable hardened oil, stearic acid, and polyethylene glycol. The tablet of claim 1, wherein the metal-free lubricant is selected from the group consisting of glyceryl bicarbonate, cured castor oil, and vegetable cured oil. The tablet according to claim 1, wherein the metal-free lubricant is present at 0.5 to 15% by weight relative to the total weight of the tablet. The method of claim 1, wherein sodium bisulfite, butylated hydroxytoluene, butylated hydroxyaniline, ascorbic acid, alpha-tocopherol, ascorbic acid palmitate, sodium ascorbate, potassium metabisulfite, propyl gallate, A tablet further comprising at least one antioxidant selected from the group consisting of sodium metabisulfite, sodium thiosulfate, and coenzyme Q10. The tablet according to claim 4, wherein the antioxidant is present in an amount of 0.1 to 20% by weight based on the total weight of the tablet. The method according to claim 1, wherein the pregelatinized starch, microcrystalline cellulose, lactose, mannitol, glucose, maltitol, dextrin, cyclodextrin, isomalt, maltodextrin, dexrate, crystalline cellulose, starch, sucrose Excipients selected from the group consisting of, low-substituted hydroxypropylmethylcellulose, chitosan, and gelatin; And at least one disintegrant selected from the group consisting of croscarmellose sodium, crospovidone, and sodium starch glyconate. A lubricant according to claim 6, wherein the lubricant is at least one selected from the group consisting of colloidal silicon dioxide and light silicic anhydride; Or a pH adjuster selected from the group consisting of glutamic acid, oxalic acid, citric acid, succinic acid, fumaric acid, tartaric acid, maleic acid, and malic acid. As a pharmaceutically active ingredient, tenofovir disoproxyl free base; Metal-free lubricants selected from the group consisting of glyceryl bicarbonate, hardened castor oil, sucrose fatty acid ester, vegetable hardened oil, stearic acid, and polyethylene glycol; And tableting a mixture comprising a pharmaceutically acceptable excipient and a disintegrant. (a) tenofovir disoproxyl free base as a pharmaceutically active ingredient; Metal-free lubricants selected from the group consisting of glyceryl bicarbonate, hardened castor oil, sucrose fatty acid esters, vegetable hardened oils, stearic acid, and polyethylene glycol; And forming dry granules with a mixture comprising a pharmaceutically acceptable excipient and a disintegrant, and (b) the granules obtained in step (a); Metal-free lubricants selected from the group consisting of glyceryl bicarbonate, hardened castor oil, sucrose fatty acid ester, vegetable hardened oil, stearic acid, and polyethylene glycol; And tableting a mixture of pharmaceutically acceptable disintegrants. 10. The method of claim 8 or 9, wherein the metal-free lubricant is selected from the group consisting of glyceryl bicarbonate, cured castor oil, and vegetable cured oil. 10. The process according to claim 8 or 9, wherein the metal-free lubricant is used at 0.5 to 15% by weight relative to the total weight of the tablet. The method of claim 8, wherein the mixture is sodium bisulfite, butylated hydroxytoluene, butylated hydroxyaniline, ascorbic acid, alpha-tocopherol, ascorbic acid palmitate, sodium ascorbate, potassium metabisulfite, propyl A method according to claim 1, further comprising an antioxidant selected from the group consisting of gallate, sodium metabisulfite, sodium thiosulfate, and coenzyme Q10. The method of claim 9, wherein the mixture of step (a) is sodium bisulfite, butylated hydroxytoluene, butylated hydroxyaniline, ascorbic acid, alpha-tocopherol, ascorbic acid palmitate, sodium ascorbate, meta And at least one antioxidant selected from the group consisting of bisulfite potassium, propyl gallate, sodium metabisulfite, sodium thiosulfate, and coenzyme Q10. The method according to claim 12 or 13, wherein the antioxidant is used in an amount of 0.1 to 20% by weight based on the total weight of the tablet. The method of claim 8, wherein the excipient is pregelatinized starch, microcrystalline cellulose, lactose, mannitol, glucose, maltitol, dextrin, cyclodextrin, isomalt, maltodextrin, dexrate, crystalline cellulose, starch, sucrose, low substituted hydroxy At least one selected from the group consisting of propylmethylcellulose, chitosan, and gelatin; The disintegrant is at least one selected from the group consisting of croscarmellose sodium, crospovidone, and sodium starch glyconate. The method of claim 9, wherein the excipient is pregelatinized starch, microcrystalline cellulose, lactose, mannitol, glucose, maltitol, dextrin, cyclodextrin, isomalt, maltodextrin, dexrate, crystalline cellulose, starch, sucrose, low substituted hydroxy At least one selected from the group consisting of propylmethylcellulose, chitosan, and gelatin; The disintegrant of step (a) and step (b) is independently one or more selected from the group consisting of croscarmellose sodium, crospovidone, and sodium starch glyconate. The lubricant of claim 8, wherein the mixture comprises at least one lubricant selected from the group consisting of colloidal silicon dioxide and light silicic anhydride; Or a pH adjusting agent selected from the group consisting of glutamic acid, oxalic acid, citric acid, succinic acid, fumaric acid, tartaric acid, maleic acid, and malic acid. A lubricant according to claim 9, wherein said mixture of step (a) comprises at least one lubricant selected from the group consisting of colloidal silicon dioxide and light silicic anhydride; Or a pH adjusting agent selected from the group consisting of glutamic acid, oxalic acid, citric acid, succinic acid, fumaric acid, tartaric acid, maleic acid, and malic acid. 10. The process according to claim 8 or 9, wherein all the processes are carried out under conditions of 60% relative humidity.