KR20170003063A - Solid formulation for oral administration containing tenofovir disoproxil and a process for the preparation thereof - Google Patents

Abstract

The present invention relates to a solid formulation for oral administration comprising wet granule containing tenofovir disoproxil or a pharmaceutically allowable salt thereof and, more specifically, to a solid formulation for oral administration containing an oxidizing agent inside or outside wet granule, and to a preparation method thereof. According to the present invention, stability of active components is excellent when the solid formulation is manufactured with a wet granule method.

Description

Technical Field [0001] The present invention relates to solid oral formulations containing tenofovir disoproxil and a process for preparing the same,

TECHNICAL FIELD The present invention relates to an oral solid preparation containing tenofovir disoproxil and a preparation method thereof, and more particularly, to a solid preparation containing tenofovir disoproxil with improved stability and a preparation method thereof.

Tenofovir disoproxil is a nucleoside analogue reverse transcriptase inhibitor that blocks reverse transcriptase, a very important enzyme in human immunodeficiency viruses HIV-1 and hepatitis B viruses. transcriptase inhibitors (NRTIs).

Tenofovir disoproxil (trade name: VIREAD, Gilead Sciences, Inc) can be used in the treatment of HIV-1 in combination with other antiviral agents and is known to be used in the treatment of chronic hepatitis B infection.

The tenofovir < RTI ID = 0.0 > disulfoxyl < / RTI > Tenofovir disoproxil is a prodrug of tenofovir and has a bis-ester form. The chemical name for tenofovir disoproxil is named 9- [2- (R) - [[bis [[(isopropoxycarbonyl) oxy] methoxy] phosphinoyl] methoxy] propyl] adenine.

[Chemical Formula 1]

In general, drugs that are salt-form but high-solubility are known to be unstable to moisture, while tenofovir disoproxil is also unstable to moisture. Therefore, if water is used in the formulation of tenofovir disoproxil, the stability of the product may be deteriorated. Therefore, it is known that it is preferable to prepare the tenofovir disoproxil by the dry granulation method for the stability of the active ingredient when granulating for formulation.

It is an object of the present invention to provide an oral solid preparation containing tenofovir disoproxil which is excellent in stability of an active ingredient when it is prepared by the wet granulation method.

Another object of the present invention is to provide a method for producing a solid pharmaceutical formulation containing tenofovir disoproxil, which is excellent in stability during production by a wet granulation method.

One aspect of the present invention is

A solid preparation for oral administration comprising wet granules comprising terbinafide disoproxil or a pharmaceutically acceptable salt thereof, wherein the wet granule contains an acidifying agent either inside the wet granule or outside the wet granule, The formulation is provided.

Another aspect of the present invention is

A granulating step of producing a wet granule comprising tenofovir disoproxil or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable additive;

A post-mixing step of preparing a mixture comprising the granulated wet granules and a pharmaceutically acceptable additive; And

Optionally, formulating the mixture,

Wherein the acidifying agent is added in the granulation step or the post-mixing step.

There is provided a method of producing an oral solid preparation according to an aspect of the present invention.

The solid formulation for enteral administration containing tenofovir disoproxil according to one aspect of the present invention can contain a acidic agent to provide a solid preparation having a markedly increased stability of the active ingredient upon solid preparation by wet granulation. Particularly, since the dry granulation method, which is capable of producing the stability of the active ingredient with excellent excellence, has a problem in that the stability is lower than that of the wet granulation method when mass-produced, the solid preparation for oral administration according to the present invention is a wet There is an advantage that it is possible to provide a solid preparation for oral administration containing Tenofovir disoproxil which is prepared by the granulation method and has improved stability of the active ingredient by an acidifying agent and is excellent in stability in mass production.

Hereinafter, the present invention will be described in more detail.

All technical terms used in the present invention are used in the sense that they are generally understood by those of ordinary skill in the relevant field of the present invention unless otherwise defined. In addition, preferred methods or samples are described in this specification, but similar or equivalent ones are also included in the scope of the present invention. The contents of all publications referred to in this specification are incorporated herein by reference in their entirety.

Since tenofovir disoproxil is a drug unstable to water, the use of water in the formulation of tenofovir disoproxil may lower the stability of the active ingredient, and therefore, it is preferable to prepare by dry granulation in granulation It was known. As a result of the study, it was found that the dry granulation method had a problem in that the production of the flexible substance was increased rather than the wet granulation method in mass production of the granules of large amount of the terbinafide disoproxil. This is because when the granules are prepared by the dry granulation method, the pressurization is caused by the compaction process for securing the flowability of the granules, that is, the productivity, which affects the physical properties of the tenofovir disoproxil, And it seems that a sharp increase occurs. As a result of studying a formulation method with high stability of an active ingredient while mass-producing it, it has been developed a solid pharmaceutical preparation of tenofovir disoproxil which is prepared by the wet granulation method and has increased stability of the active ingredient, Thereby making it possible to provide a solid preparation in which the stability of the active ingredient is ensured.

The present invention, in one aspect,

A solid preparation for oral administration comprising a wet granule comprising tenofovir disoproxil or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the wet granule comprises an acidic agent inside the wet granule or outside the wet granule A solid preparation for administration is provided.

The pharmaceutically acceptable salt includes an acid addition salt, and the acid addition salt includes an inorganic acid salt or an organic acid salt.

The inorganic acid salt includes, but is not limited to, hydrochloride, phosphate, sulfate or disulfate. The organic acid salt may be at least one selected from the group consisting of fatty acid salts such as acetate, dichloroacetate, adipate, alginate, ascorbate, camphorate, caprate, caproate, caprylate, cyclamate, galactarate, glucoside, glucuronate , Glutamate, oxoglutarate, lactobionate, thiocyanate, malonate, uronate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, heptanoate, But are not limited to, lactose, malonate, succinate, suberate, sebacate, maleate, orotate, myristate, butyne-1,4-dioate, hexyne-1,6-dioate, citrate, lactate, Butyrate, glycolate, maleate, tartrate; Methanesulfonate, propanesulfonate, camposulfonate, camsylate, eddylate, escitalate, isethionate, which are aliphatic sulfone organic acid salts; Aromatic organic acid salts such as benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, phenylacetate, phenylpropionate, phenylbutyrate, mandelate, salicylate , Para-aminosalicylate, tannate, cinnamate; But are not limited to, aromatic sulfonic organic acid salts such as benzene sulfonate, toluene sulfonate, xylene sulfonate, naphthalene-1-sulfonate, or naphthalene-2-sulfonate.

In one embodiment, the pharmaceutically acceptable salt of tenofovir disoproxil may be a phosphate, orotate, a fumarate or a succinate.

In one embodiment, the pharmaceutically acceptable salt of the tenofovir disoproxyl is a phosphate.

As used herein, an "acidifying agent" is any material that lowers the pH of a solution upon dissolution in water. In one embodiment, the acidifying agent is an inorganic acid and / or an organic acid capable of lowering the pH of the solution to 5 or less when dissolved in water.

The inorganic acid includes, but is not limited to, hydrochloric acid, phosphoric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, or any combination thereof. Wherein the organic acid is selected from the group consisting of citric acid, lactic acid, tartaric acid, fumaric acid, phthalic acid, acetic acid, oxalic acid, malonic acid, adipic acid, fucic acid, succinic acid, glutaric acid, maleic acid, malic acid, mandelic acid, ascorbic acid, Include capric, caproic, caprylic, lauric, arachidic, erucic, linolic, linolenic, oleic, palmitic, myristic, edicic, stearic, or any combination thereof However, the present invention is not limited thereto.

In one embodiment, the acidifying agent is an organic acid having 2 to 20 carbon atoms including a carboxyl group (COOH) or a sulfonic group (SO ₃ H).

In one embodiment the acidifying agent is selected from the group consisting of acetic acid, adipic acid, citric acid, ascorbic acid, erythorbic acid, lactic acid, propionic acid, tartaric acid, fumaric acid, formic acid, oxalic acid, camsylic acid, malic acid, And any combination thereof.

In one embodiment, the acidifying agent may be selected from the group consisting of citric acid, erythorbic acid, fumaric acid, tartaric acid, and any combination thereof. In one embodiment, the acidifying agent is tartaric acid.

The amount of the acidifying agent in the solid preparation for oral administration was measured by dissolving the solid preparation in 900 ml of purified water according to the paddle method of the USP dissolution test item for 30 minutes The pH of the post-elution solution may be 1 to 5, and the specific amount may vary depending on the kind of the acidic agent. For example, the acidifying agent may be included in an amount of about 0.045 to 0.1 part by weight based on 1 part by weight of the active ingredient tenofovir disoproxil free base.

In one embodiment, the tartaric acid may be included in an amount of about 0.045 to 0.1 parts by weight based on 1 part by weight of the tenofovir disoproxil free base.

In one embodiment, when the dissolution test is carried out using 900 ml of purified water according to the paddle method of USP (USP) dissolution test item, the solid preparation for oral administration is administered after 30 minutes, lt; RTI ID = 0.0 > 1 < / RTI >

The above-mentioned solid preparation for oral administration according to the present invention can remarkably increase the stability of tenofovir disoproxil over time by containing an acidifying agent in the wet granule or containing an acidifying agent on the outside of the wet granule. As a result of the test, the solid preparations for oral administration containing tenofovir disoproxil containing an acidic agent showed a tendency to decrease the amount of the produced substance with time over a period of time as compared with the case of not containing an acidifying agent or not containing a sufficient amount of an acidifying agent (See Tables 9 and 10). In addition, the stability of the active ingredient in the mass production of the tenofovir disoproxil solid preparation by the dry granulation method was lower than that of the wet granulation method by the dry granulation method. (See Table 7). Therefore, the solid preparation according to the present invention can provide a solid preparation for enteropathy comprising tenofovir disoproxil in which the stability of the active ingredient is increased upon mass production.

The term "mass production" as used herein refers to an amount of the dry granulation method when the preparation of the tenofovir disoproxil is performed to a degree that the stability of the active ingredient is rather lower than that produced by the wet granulation method, The conditions of the dry granulation method including the size of the roller compactor, and the like. In one embodiment, the mass production means 20 kg or more per granule per batch.

In one embodiment, the solid formulation has a water content of less than 1% by weight of the wet granulate containing it. When the water content of the wet granule exceeds 1% by weight, the generation of the flexible substance of the active ingredient increases remarkably with the elapse of time, so that it is preferable that the water content is 1% by weight or less. However, even if the water content of the wet granules exceeds 1% by weight due to the failure in control of the water content, the solid preparation can remarkably lower the degree of increase of the flexible substance due to the presence of the acidifying agent, (See Tables 8 and 10).

In one embodiment, the solid formulation has a water content of less than 2% by weight of the wet granulate containing it. As a result of the experiment, even when the water content of the wet granules contained in the solid preparation is 2% by weight, the degree of increase of the softening substance can be remarkably lowered due to the inclusion of the acidifying agent, so that a stable solid preparation can be provided ).

In the present specification, the term "solid preparation" means a preparation which is formed by molding or spraying the drug into a certain shape. The oral solid preparations can be formulated into, for example, pellets, capsules, tablets (including single-layer, double-layer, and inner-wall tablets), dry syrup, granules and the like, but are not limited thereto. More specifically, the oral solid combination preparation may be in the form of a capsule, a single-layer tablet or a two-layer tablet. When the oral solid preparation for oral use is a capsule, the capsule may be in the form of granules or tablets. In one embodiment, the solid preparation for oral administration is a tablet.

In one embodiment, the solid preparation for oral administration is a solid preparation for oral administration comprising a wet granule comprising a terbinafide disulfonic acid phosphate, wherein the wet granule or the wet granule is coated with tartaric acid as an acidifying agent 0.045-0.1 parts by weight based on 1 part by weight of free base diisopropylxyl free base.

In one embodiment, the solid preparation for oral administration is a solid preparation for oral administration comprising a wet granule comprising a terbinafide disulfonic acid phosphate, wherein the wet granule or the wet granule is coated with tartaric acid as an acidifying agent 0.045-0.1 part by weight based on 1 part by weight of the free base diisopropylxyl free base, and the content of water in the wet granule is not more than 2% by weight based on the whole granules.

In one embodiment, the solid preparation for oral administration is a solid preparation for oral administration comprising a wet granule comprising a terbinafide disulfonic acid phosphate, wherein the wet granule or the wet granule is coated with tartaric acid as an acidifying agent 0.045-0.1 part by weight based on 1 part by weight of free base diisopropylxyl free base, and the content of water in the wet granule is 1% by weight or less with respect to the whole granules.

The solid preparation for oral administration may further comprise at least one pharmaceutically acceptable additive in addition to the active ingredient and the acidifying agent. Specifically, the pharmaceutically acceptable additive may further comprise at least one substance selected from the group consisting of a diluent, a binder, a disintegrant, a lubricant, and any combination thereof.

The diluent may be selected from the group consisting of mannitol, lactose, starch, microcrystalline cellulose, ruddy press, calcium dihydrogenphosphate, and any combination thereof, but is not limited thereto. The diluent may be contained in an amount of 1 to 99% by weight, preferably 20 to 80% by weight, based on the total weight of the solid preparation.

The binder may be selected from the group consisting of povidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, pregelatinized starch, polyvinyl alcohol, carboxymethylcellulose sodium, and any combination thereof, but is not limited thereto . The binder may be included in an amount of 0.5 to 10% by weight, preferably 1 to 5% by weight, based on the total weight of the solid preparation.

The disintegrant may be selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, and any combination thereof, but is not limited thereto. The disintegrant may be used in an amount of 0.5 to 50% by weight, preferably 1 to 30% by weight, based on the total weight of the solid preparation.

The lubricant may be selected from the group consisting of stearic acid, metal salts of stearic acid (e.g., calcium stearate, magnesium stearate), talc, colloidal silica, sucrose fatty acid ester, hydrogenated vegetable oil, wax, glyceryl fatty acid esters, glycerol dibehenate, And any combination thereof. However, the present invention is not limited thereto. The lubricant may be included in an amount of 0.3 to 10% by weight, preferably 0.5 to 5% by weight, based on the total weight of the solid preparation.

In one embodiment, the oral solid preparation may contain about 0.1-500 mg of the active ingredient per unit dosage form of tenofovir disoproxyl or a pharmaceutically acceptable salt thereof as the free base, and the total weight of the solid preparation By weight, based on the total weight of the composition, of 0.5 to 60% by weight, specifically 1 to 50% by weight.

The oral solid preparation can be administered to a mammal, including a human, having any indication of tenofovir disoproxil or a pharmaceutically acceptable salt thereof. Thus, the oral solid preparation can be used for the treatment of HIV-1 or chronic hepatitis B, but is not limited thereto.

The oral solid preparations according to the present invention may be prepared according to the methods for preparing solid preparations, specifically granules, dry syrups, pellets, capsules, or tablets, which are known in the art. In one embodiment, wet granules can be prepared according to the process for the preparation of oral solid preparations using them.

According to another aspect of the present invention,

A granulating step of preparing a wet granule comprising tenofovir disoproxil or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive;

A post-mixing step of preparing a mixture comprising the granulated wet granules and a pharmaceutically acceptable additive; And

Optionally, formulating the mixture,

Wherein an acidifying agent is added in the granulation step or in the post-mixing step, according to an aspect of the present invention.

The details of the method for producing the oral solid preparation according to this aspect can be applied as the description of the oral solid preparation according to one aspect of the present invention as it is.

The granule preparation step may be manufactured according to any wet granule manufacturing method known in the art.

The wet granulation method may be carried out by granulating a mixture containing tenofovir disoproxil or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive into a binding liquid, and drying the resultant. The acidifying agent may be added to the mixture, the bonding liquid, or both the mixture and the bonding liquid.

The pharmaceutically acceptable additives used in the granulation step may be selected from diluents, binders, disintegrants, and any combination thereof.

The solvent for preparing the binding solution may be water, ethanol, isopropanol, acetone, or a combination thereof. In addition to the binder, the binding liquid may be prepared by adding to the solvent additional additives commonly used in the pharmaceutical field, for example, a surfactant, a buffer, or a combination thereof. According to one embodiment, the binding liquid is water, specifically purified water.

The drying process is preferably carried out at a temperature which does not exceed about 60 캜, preferably not more than about 50 캜, more preferably not more than about 40 캜, most preferably not more than 20 For example, by air drying, fluid bed drying, oven drying or microwave drying at a temperature of from < RTI ID = 0.0 > 40 C < / RTI >

In one embodiment, the drying process can dry the granules to contain no more than 2% water by weight.

In one embodiment, the drying process may be such that the granules contain up to 1% by weight of water.

In the post-mixing step of mixing the wet granules with the pharmaceutical additive, the additive may be a disintegrant and / or a lubricant. In one embodiment, the disintegrant is crospovidone. In one embodiment, the lubricant is a sucrose fatty acid ester. Such an acidifying agent may be added and mixed in the subsequent mixing step.

The formulation may be carried out according to any method known in the art for the formulation of a solid preparation using granules and may be carried out by any known method of formulation into, for example, tablets, capsules, or dry syrups . In one embodiment, the step of formulating is a step of preparing the tablet.

In one embodiment, the method of making the solid formulation is a method of producing granules in a mass production of 20 kg or more per granule per batch. Through the above-described production method, it is possible to produce an oral solid preparation having excellent stability of the active ingredient as compared with the mass production by the dry granulation method while mass-producing it.

Hereinafter, the present invention will be described in detail based on the following examples. However, the following examples are intended to illustrate the present invention, but the scope of the present invention is not limited thereto.

Manufacturing example  1 to 4: Granulation method  And production of granules and tablets according to yield

Granules were prepared with the equipment and scale, process parameter values shown in Table 1 below. 100 mg of terbinafide disoproxil phosphate, 40 mg of microcrystalline cellulose, 55 mg of lactose, and 10 mg of pregelatinized starch were prepared per unit dosage form of the final tablets obtained, and 100 mg of purified water was used in the wet granulation method .

In case of the dry granulation method, the active ingredient and the additives are sieved with a 20 mesh sieve, and the granules are dry-granulated using a roller compactor under the above conditions. The granules are pulverized by an oscillator 20 mesh And then granulated to prepare granules.

In the case of the wet granulation method, the active ingredient and the additives are sieved with a 20 mesh sieve, and the mixture is put into a fluid bed granulator. The purified water is sprayed in the spraying conditions to granulate the granules, ) 20 mesh to prepare granules.

Manufacturing example Granule
quite
Facilities and Scale Process parameter setting value Granule moisture (%) One deflation Roller compactor
(TF-1-A60, FREUND VECTOR)
Production efficiency: ~ 1kg / hr Roll rate: 2 rpm
Feeding rate: 20 rpm
Hydraulic: 5 Mpa 0.8
(theory
moisture
maintain) 2 Roller compactor
(WP160x60, Turbo kogyo)
Production efficiency: ~ 55kg / hr Roll rate: 13 rpm
Feeding rate: 35 rpm
Hydraulic: 6 Mpa 33 Wet Fluid bed granulator
(NQ-160, Dalton)
Capacity: 200 - 700g Product temperature: 30 ℃
Spray pressure: 0.8 bar
Spray rate: 10 rpm
Drying temperature: 45 ° C

0.8
(theory
Moisture and
equally
dry) 4 Fluid bed granulator
(GRTEC 30, GR-ENG)
Capacity: 10 - 16kg Product temperature: 30 ℃
Spray pressure: 1.0 bar
Spray rate: 15 rpm
Drying temperature: 45 ° C

The granules thus prepared were mixed with the granules of crospovidone and sucrose fatty acid ester to prepare 10 mg of crospovidone and 2 mg of sucrose fatty acid ester per tablet, and the tablets were prepared by tableting.

Manufacturing example  5 to 9: In the wet granulation method  Of granules and tablets

Wet granules and tablets were prepared in the same manner as in Preparation Example 3, except that the water content of the granules was varied at the facility and scale shown in Table 2 below.

Granule manufacturing method Facilities and Scale Granule moisture (%) Production Example 5 Wet Fluid bed granulator
(NQ-160, Dalton)
Capacity: 200-700g 0.5 Production Example 3 0.8 Production Example 6 1.0 Production Example 7 1.5 Production Example 8 2.0 Production Example 9 2.5

Example  1 to 4: Preparation of Granules and Tablets by Addition of Granular External Acidifying Agent

In the same manner as in Production Example 8 except that the wet granules were mixed with the crospovidone and the sucrose fatty acid ester after the preparation of the wet granules, the wet granules and Tablets were prepared.

Granule
quite Facilities and Scale Granule
moisture
(%) Acidifying agent (mg) Production Example 8 Wet Fluid bed granulator
(NQ-160, Dalton)
Capacity: 200-700g 2.0 X Example 1 Citric acid 4.5 Example 2 Eri sorbic acid 4.5 Example 3 Fumaric acid 4.5 Example 4 Tartaric acid 4.5

Example  5 to 8: Preparation of Granules and Tablets by Introducing Acidifying Agents in Granules

In the same manner as in Production Example 8, except that the amount of the acidifying agent was dissolved in the purified water in the preparation of the wet granules in Preparation Example 8 to prepare wet granules by spraying the same, the wet granules and the tablets .

Granule
quite Facilities and Scale Granule moisture
(%) Using acidic agents
(mg) Production Example 8 Wet Fluid bed granulator
(NQ-160, Dalton)
Capacity: 200-700g 2.0 X Example 5 Citric acid 4.5 Example 6 Eri sorbic acid 4.5 Example 7 Fumaric acid 4.5 Example 8 Tartaric acid 4.5

Example  9 to 12: Preparation of Granules and Tablets by Addition of Various Amounts of Granular Foreign Acid Agent

In the same manner as in Production Example 8, except that the wet granules after preparation of wet granules were mixed with crospovidone and sucrose fatty acid ester, and the content of the tartaric acid shown in the following Table 5 was added together and mixed, Wet granules and tablets were prepared as indicated.

Granule
quite Facilities and Scale Granule moisture
(%) Tartaric acid
(mg) Production Example 8 Wet Fluid bed granulator
(NQ-160, Dalton)
Capacity: 200-700g 2.0 X Example 9 2.0 Example 4 4.5 Example 10 7.0 Example 11 9.5 Example 12 11.0

Test Example  One: pH  Comparative evaluation

The tabofovir tablets obtained in Production Example 8 and Examples 1 to 12 were subjected to a dissolution test using 900 ml of purified water according to the paddle method of the USP dissolution test item. The pH of the dissolution test solution was measured 30 minutes after the start of the test and is shown in Table 6 below.

Manufacturing example Example 8 One 2 3 4 5 6 7 8 9 10 11 12 pH 5.6 3.8 3.6 3.9 4.0 3.6 3.8 3.8 3.6 5.2 3.6 3.5 3.3

As can be seen from Table 6 above, Examples 1 to 12 using the acidifying agent showed that the elution test solution showed a pH lower than pH 5.0 after 30 minutes from the start of the test except for Example 9, and that the acidifying agent was not used, In Production Examples 8 and 9 using a topping agent, the pH of the dissolution test liquid was found to be higher than pH 5.0.

Test Example  2: Flexible  evaluation

The tabofiole tablets obtained in Production Examples 1 to 9 and Examples 1 to 12 were subjected to the measurement of the amount of unknown suppository to evaluate the storage stability. After the HDPE bottle was packaged, the formulation was stored in a chamber at 60 ° C for 1 hour, 2 weeks, and 4 weeks to observe the change with time to predict storage stability.

The measurement of the amount of unknown substance was carried out under the following test conditions.

<Test Conditions>

Detector: ultraviolet absorption spectrophotometer (measuring wavelength: 260 nm)

Column: ODS-2 C18 250 mm column

Flow rate: 1.0 ml / min

Column temperature: 35 ° C

Analysis time: 60 minutes

The measurement results are shown in Tables 7 to 10 below.

Table 7 shows the results of the measurement of the time course of the tablets according to granule production method and facility size.

Exposure period Start 60 ℃ 1 week exposure 60 ° C 2 week exposure 60 ℃ 4 weeks exposure Production Example 1 0.00 0.01 0.03 0.07 Production Example 2 0.00 0.12 0.25 0.38 Production Example 3 0.00 0.03 0.08 0.16 Production Example 4 0.00 0.04 0.07 0.15

According to the above Table 7, tablets containing granules produced by the wet granulation method exhibited similar forms of producing a flexible substance regardless of the production scale. However, in the case of tablets containing granules produced by the dry granulation method, The increase of the flexible material was found to be larger. It is believed that the active ingredient becomes unstable due to the increase in pressure applied to the active ingredient as the production scale increases.

Table 8 shows the results of the measurement of the time course of the tablet according to the water content of the granules obtained by the wet granulation method.

Exposure period Start 60 ℃ 1 week exposure 60 ° C 2 week exposure 60 ℃ 4 weeks exposure Production Example 5 0.00 0.03 0.06 0.13 Production Example 3 0.00 0.03 0.08 0.16 Production Example 6 0.00 0.04 0.09 0.16 Production Example 7 0.00 0.06 0.14 0.32 Production Example 8 0.00 0.13 0.26 0.41 Production Example 9 0.00 0.20 0.31 0.49

According to the above Table 8, it was confirmed that the tablets containing the granules prepared by the wet granulation method had a large increase in the amount of the suppositories when the water content of the granules exceeded 1.0%. This seems to be due to the fact that moisture promotes decomposition of the active ingredient. Therefore, it is preferable to maintain the water content of the granules at 1.0% by weight or less at the time of producing the wet granules in order to produce a drug having high stability of the active ingredient.

Table 9 below shows the measurement results of the time-dependent softening substances of the tablets prepared by adding acidifying agents or adding various acidifying agents when wet granulating tablets were prepared in the production of wet granules.

Exposure period Start 60 ℃ 1 week exposure 60 ° C 2 week exposure 60 ℃ 4 weeks exposure Production Example 8 0.00 0.13 0.26 0.41 Example 1 0.00 0.17 0.29 0.31 Example 2 0.00 0.11 0.12 0.19 Example 3 0.00 0.06 0.14 0.16 Example 4 0.00 0.05 0.09 0.15 Example 5 0.00 0.12 0.21 0.28 Example 6 0.00 0.10 0.15 0.24 Example 7 0.00 0.11 0.17 0.18 Example 8 0.00 0.04 0.10 0.17

According to the above Table 9, it was found that the increase in the amount of the flexible substance in the tablet was significantly reduced compared to that in Production Example 8 in which the acidifying agent was not used, irrespective of whether the acidifying agent was contained in the granules or contained outside the granules. In addition, even though the water content of the granules was 2%, the contents of the purified substances in the various acidifying agents were significantly reduced compared with those in Preparation Example 8, which was an acidifying agent unused tablets. Therefore, it is expected that a drug having high stability can be produced even when water is not controlled in the production of wet granules.

Table 10 shows the results of measurement of the time-dependent softening substance of tablets prepared by adding various amounts of tartaric acid as an acidifying agent in the production of wet granules.

Exposure period Start 60 ℃ 1 week exposure 60 ° C 2 week exposure 60 ℃ 4 weeks exposure Production Example 8 0.00 0.13 0.26 0.41 Example 9 0.00 0.10 0.19 0.32 Example 4 0.00 0.05 0.09 0.15 Example 10 0.00 0.04 0.07 0.14 Example 11 0.00 0.02 0.07 0.15 Example 12 0.00 0.03 0.05 0.12

According to Table 10, when tartaric acid was used as an acidifying agent, it was found that there was a difference in production amount of the active ingredient-containing substance depending on the amount used. The use of tartaric acid in an amount of more than 0.045 part by weight per 100 parts by weight of the active ingredient is preferable because the amount of the softening agent is significantly reduced. However, when the amount is more than 0.1 part by weight, the flowability of the final mixture is deteriorated due to the physical properties of tartaric acid. It can have a bad influence. The flowability of the granules can be judged from the Hausner ratio, which can be calculated from the density (Hausner ratio = Tapped density / Bulk density). Over 0.1 part by weight of tartaric acid shows a value of 1.35 - 1.45 and Flow character 'Poor' 1.19 - 1.25 at lower usage than weight and good flow which means Flow character 'Fair'. Thus, tartaric acid is believed to be suitable in an amount of 0.045 - 0.1 parts by weight relative to the active ingredient.

The present invention has been described with reference to the preferred embodiments. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the above-described embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.

Claims (15)

A solid preparation for oral administration comprising a wet granule comprising tenofovir disoproxil or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the wet granule comprises an acidic agent inside the wet granule or outside the wet granule A solid preparation for administration. The solid preparation according to claim 1, wherein the acidifier is an organic acid having 2 to 20 carbon atoms including a carboxyl group (COOH) or a sulfonic group (SO ₃ H). 3. The method of claim 2, wherein the acidifier is selected from the group consisting of acetic acid, adipic acid, citric acid, ascorbic acid, erosorbic acid, lactic acid, propionic acid, tartaric acid, fumaric acid, formic acid, oxalic acid, camsylic acid, malic acid, &Lt; / RTI &gt; and any combination thereof. 3. The solid preparation according to claim 2, wherein the acidifying agent is selected from the group consisting of citric acid, erythorbic acid, fumaric acid, tartaric acid, and any combination thereof. The solid preparation according to claim 1, wherein the wet granule has a water content of 2% by weight or less. The solid formulation according to claim 1, wherein the wet granulate is produced in a mass production of 20 kg or more per granule per batch. The method according to claim 1, wherein when the solid preparation is subjected to a dissolution test using 900 ml of purified water according to the paddle method of USP dissolution test item, the pH of the dissolution solution after 30 minutes is RTI ID = 0.0 &gt; 1 &lt; / RTI &gt; The solid preparation according to claim 1, wherein the acidifying agent is contained in an amount of 0.045 to 0.1 part by weight based on 1 part by weight of the cannabisisopropyl isomer. The solid preparation according to claim 1, wherein the solid preparation is a granule, a capsule, or a tablet. The solid formulation of claim 1, further comprising a pharmaceutically acceptable additive selected from the group consisting of a diluent, a binder, a disintegrant, a lubricant, and any combination thereof. The composition of claim 10, wherein the diluent comprises 20 to 80 wt%, the binder is 1 to 5 wt%, the disintegrant is 1 to 30 wt%, or the lubricant is 0.5 to 5 wt% Solids &lt; / RTI &gt; The solid preparation according to claim 1, which is for the treatment of HIV-1 or chronic hepatitis B. A granulating step of preparing a wet granule comprising tenofovir disoproxil or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive;
A post-mixing step of preparing a mixture comprising the granulated wet granules and a pharmaceutically acceptable additive; And
Optionally, formulating the mixture,
Wherein the acidifying agent is added in the granulation step or the post-mixing step.
13. A method for producing a solid preparation for oral use according to any one of claims 1 to 12. 14. The method according to claim 13, further comprising drying the granules after the granulating step so as to contain not more than 2% by weight of water. 14. The method of claim 13, wherein the pharmaceutically acceptable additive is selected from the group consisting of a diluent, a binder, a disintegrant, a lubricant, and any combination thereof.