KR101033975B1 - Method for preparation of solid oral dosage forms of valsartan using the direct compression method and solid oral dosage forms thereby - Google Patents

Abstract

The present invention relates to a process for preparing valsartan-containing solid oral dosage forms by direct compression and to solid oral dosage forms prepared thereby, and the production of oral solid dosage forms containing valsartan by direct compression using hydroxypropylcellulose as a binder , It is possible to solve the time and economic problems caused by the conventional granule compression method, and it is possible to manufacture tablets having excellent hardness and high degree of grindability, which is very useful in the fields of medicine and medicine.

Valsartan, hydroxypropylcellulose, binder, direct compression method, oral formulation

Description

[0001] The present invention relates to a method for preparing valsartan-containing solid oral dosage forms using a direct compression method and a solid oral dosage form prepared thereby,

The present invention relates to a process for the preparation of solid oral formulations of valsartan by direct compression and to solid oral formulations prepared thereby, and more particularly to a pharmaceutical oral dosage form comprising valsartan or a pharmaceutically acceptable salt thereof, The present invention relates to a method for producing a valsartan-containing solid oral dosage form prepared by direct compression method with addition of propylcellulose, and a solid oral dosage form prepared by the method and having improved margins and drug dissolution rate.

Valsartan (molecular formula: C ₂₄ H ₂₉ N ₅ O ₃ , molecular weight: 435.519) represented by the following formula 1 is an angiotensin II receptor antagonist and is effective in the treatment of congestive heart failure and lowers blood pressure regardless of age, sex, or race It is known to be effective, and is also well tolerated and well tolerated by the human body.

Presently, the valsartan is marketed by Novartis as an oral formulation called " Diovan ", and occupies the largest market share as shown in Table 1 below.

ARB-type hypertension drug market (Unit: billion) company subject First quarter of 2008 1Q 2007 Novartis Diovan 131 126 Sanofi-aventis Afro Bell 101 106 Novartis Cody Ovain 96 77 MSD Koza 91 87 Daewoong Pharmaceutical Olmetec 83 61 Sanofi-aventis Core Pro Bell 81 73 MSD Coza Plus 80 77 AstraZeneca Atakan 75 64 Daewoong Pharmaceutical Olmetec Plus 73 43 AstraZeneca Atakan Plus 61 49

Korean Patent No. 10-0659644 discloses a pharmaceutical composition containing valsartan as an active ingredient, crospovidone as a disintegrant, microcrystalline cellulose as a binder, Aerosil 200 as a sliding agent, and magnesium stearate (magnesium stearate) as a lubricant Korean Patent No. 10-0618038 discloses an oral dosage form containing low-substituted hydroxypropylcellulose as a disintegrant in valsartan as an active ingredient, microcrystalline cellulose as a binder, aerosil as a sliding agent, lubricant Magnesium stearate, talc, and the like.

These patents disclose solid oral formulations by dry granulation compression. That is, the method comprises the steps of pulverizing an effective ingredient and a pharmaceutically acceptable additive, compressing the pulverized mixture to a minimum denudation force to form a co-primeate, converting the resulting co-primeate into a granule, Lt; RTI ID = 0.0 > oral < / RTI > formulation.

However, the dry granule compacting method is somewhat complicated and requires additional equipment, which is disadvantageous in terms of time and cost. This is because the valsartan-containing solid dosage form has a low degree of grindability, so that the dry granule compacting method can not be applied. Therefore, a new method for improving this is required.

Methods for preparing conventional pharmaceutical solid oral formulations include direct compression and granular compression.

The direct compression method is to prepare a solid oral dosage form by directly tabletting a uniform dry mixture prepared by mixing additives such as excipients, binders, disintegrants, etc. into crystals or powders of the active ingredient. There is no advantage.

On the other hand, the granule compression method is a method of preparing granules by mixing an active ingredient and a pharmaceutical additive and then tableting the granules. The granular compression method is usually used when the fluidity of the pharmaceutical composition is poor or when the binding force is weak. The granular compression method can be divided into a dry method and a wet method. The dry method is a method in which a slug and a sheet material produced by dry granulation are pulverized and sized to mix a lubricant and compressed. In the wet method, an excipient, a disintegrant, or the like is added to a pharmaceutical product, The size of the granules is fixed by using a machine, and then the granules are granulated. However, such a granular compression method is complicated in manufacturing process as compared with the direct compression method, and requires much time and facilities. Also, there is a high likelihood that the active ingredient will be degraded during the granulation process. Thus, for this reason, the direct compression method is considered to be economical and ideal.

However, one of the biggest obstacles to the production of solid oral dosage forms by direct compression is the binding force of pharmaceutical compositions. If the binding force is not sufficient, the tablets will not be formed upon compression with the tablet, or capping or laminating will appear. Even if tablets are formed, the tablets may be worn or broken in subsequent processes such as coating and packaging, resulting in loss of commercial value. Thus, the binding force between the pharmaceutical compositions in a solid oral formulation can be a very important factor to be directly linked to the final market. If the direct compression method does not have a binding force capable of producing a solid oral dosage form, it will inevitably follow the granulation method.

In the case of the conventional valsartan oral solid dosage form, the granular compression method has only to be applied because it does not have the appropriate components and composition ratios to apply the direct compression method.

Accordingly, the inventors of the present invention found that, when researching a valsartan-containing solid oral dosage form, it is possible to control the appropriate components and content and to apply a direct compression method when hydroxypropyl cellulose is used as a binder, The present inventors completed the present invention by confirming that the oral solid preparation of valsartan was prepared and that the prepared solid oral formulation had a low degree of fining and an excellent dissolution rate.

It is an object of the present invention to provide a process for preparing a solid oral dosage form containing valsartan by direct compression.

It is still another object of the present invention to provide a solid oral dosage form containing valsartan, which is produced by the above-described method and has excellent scratch resistance.

In order to achieve the above object, the present invention provides a method for preparing a solid oral dosage form containing valsartan by direct compression method.

The present invention also provides a solid oral dosage form containing valsartan, which is produced by the above process and has excellent masness.

The present invention relates to a process for preparing valsartan-containing solid oral dosage forms by direct compression and to solid oral dosage forms prepared thereby, and the production of oral solid dosage forms containing valsartan by direct compression using hydroxypropylcellulose as a binder , It is possible to solve the time and economic problems caused by the conventional granule compression method, and it is possible to manufacture tablets having excellent hardness and high degree of grindability, which is very useful in the fields of medicine and medicine.

Hereinafter, the present invention will be described in detail.

The present invention provides an effective amount of valsartan or a pharmaceutically acceptable salt thereof; Fillers; Disintegration; slush; And a binder, hydroxypropyl cellulose, and mixing (step 1); And

And a step of molding the mixture by a direct compression method to prepare a solid oral dosage form (step 2). The present invention also provides a method for producing a solid oral dosage form containing valsartan by direct compression.

Step 1 of the present invention is a step of mixing valsartan and other additives to apply a direct compression method.

An " effective amount " of valsartan or a pharmaceutically acceptable salt thereof of said step 1 means an amount that stops or reduces the progress of the condition to be treated or otherwise fully or partially treats or alleviates the symptoms. Such an amount can be determined by a suitable effective amount test from the point of view of a person skilled in the art, but a preferable effective amount may be 40 to 60% by weight.

The solid oral formulations of the present invention comprise an effective amount of valsartan or a pharmaceutically acceptable salt thereof and fillers, disintegrants, lubricants and binders as essential ingredients, but in addition to the above-described ingredients, additives known in the art to which the present invention pertains . ≪ / RTI >

Suitable fillers for the compositions of the present invention may be selected from the group consisting of refined powdered sugar, pressed sugar, dextrates, dextrin, dextrose, lactose, mannitol, microcellulose such as Avicel ( ^TM ), or powdered cellulose, sorbitol, sucrose And talc may be used. A preferred filler may be microcellulose. The filler is preferably added in an amount of 25 to 35% by weight.

Suitable disintegrants for the compositions of the present invention include, but are not limited to, carboxymethylcellulose-calcium (CMC-Ca), carboxymethylcellulose-sodium (CMC-Na), crosslinked PVP (crospocidone, polyplasdone, , Alginic acid, sodium alginate, and guar gum. The preferred disintegrant is crospovidone. The disintegrant is preferably added in an amount of 10 to 15% by weight.

The lubricant suitable for the composition of the present invention may be any one selected from the group consisting of magnesium stearate, aluminum stearate, calcium stearate, polyethylene glycol (PEG) having a molecular weight of 4,000 to 80,000, and talc. A preferred lubricant is magnesium stearate.

Suitable binders for the compositions of the present invention include, but are not limited to, starches such as potato starch, wheat starch or corn starch, microcrystalline cellulose, for example known under AviecelTM, FiltrakTM, HewetenTM or PharmacelTM. Hydroxypropylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose, such as hydroxypropylcellulose having a hydroxypropyl content of 5 to 16% by weight and a molecular weight of 80,000 to 1,150,000, more specifically 140,000 to 850,000, And may be any one or more selected from the group consisting of A preferred binding agent is hydroxypropylcellulose.

The hydroxypropyl cellulose is a polyhydroxypropyl ether derivative of cellulose, and is a pharmacological additive that is physically and chemically stable and has low toxicity and is commonly used in the field of pharmacy. Particularly, hydroxypropyl cellulose used as a binding agent of the present invention has a role of enhancing the margins by imparting a binding force to a pharmaceutical formulation containing valsartan.

Such hydroxypropyl cellulose is commercially available in various grades depending on the degree of polymerization of hydroxypropyl ether, and physical properties such as viscosity and molecular weight vary depending on the degree of polymerization. The degree of polymerization of the hydroxypropyl ether of low-substituted hydroxypropyl cellulose, which is usually used as a disintegrant in the pharmaceutical field, is 5.0 to 16.0%, which is distinguished from hydroxypropyl cellulose in terms of physical properties and uses.

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The additives such as the filler of the present invention preferably have a certain component range in order to perform the direct compression method. That is, for example, the amount of filler may vary from 25 to 35% by weight; The amount of disintegrant may vary from 10 to 15% by weight; The amount of lubricant may vary from 2 to 3% by weight; The amount of binder may vary from 3 to 10% by weight.

In step 1 of the production method of the present invention, the pulverization can be carried out according to the conventional method of fractionation or differentiation. Valsartan and other additives may be milled individually or together and then sized to a size of 0.1 to 200 μm. This can be done by conventional grinding methods, such as air jet mills, hammer and screen mills, fine impact mills, ball mills or vibrators mill. < / RTI > The differentiation method is preferably carried out, for example, by a known method using an ultrasonic grinder in the form of a BRANSON sonifier, or by stirring a high speed stirrer, for example a stirrer roll suspension of the HOMOREX type. The ground particles may be further sieved and mixed.

Step 2 of the manufacturing method according to the present invention is a step of molding a mixture of step 1 by a direct compression method to prepare a solid oral dosage form. The "direct compression method" is a concept in contrast to the "granule compression method" which is a method of directly granulating a dry mixture of an active ingredient and an additive, and then granulating the granule with an active ingredient and additives.

The direct compression method may be performed using a rotary tablet machine, and may be performed at a pressure of 30 to 90 KN during the rotary tablet machine. More preferably 50 to 70 KN.

The compositions of the present invention are useful for the treatment of hypertension (either malignant, essential, neovascular, diabetic, isolated systolic or other secondary types), congestive heart failure, angina pectoris (stability or instability), myocardial infarction, atherosclerosis, diabetic nephropathy , Diabetic cardiomyopathy, renal failure, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction (e. G., Alzheimer's disease) and diaphoresis.

The oral oral dosage form containing valsartan prepared by the direct compression method using the hydroxypropylcellulose of the present invention as a binding agent has a marginality of 0.5% or less, specifically 0.3% or less, which is far superior to a conventionally known composition (See Table 5). In addition, the drug release was superior to a conventionally known composition and exhibited a drug release pattern most similar to that of a commercial formulation (see FIG. 1). In addition, as a result of the stability test conducted according to KFDA notification standard, it was found to be stable to the same level as that of the commercial product (see Table 6).

Therefore, it is considered that the solid oral dosage form of the present invention is effective in terms of preparation time and cost, and also has excellent dissolution rate, thereby effectively replacing the conventionally known composition.

Hereinafter, the present invention will be described in detail with reference to examples, but the scope of the present invention is not limited to these examples.

Example  1 to 3: Direct compression method Valsartan  Of oral solid dosage form

The components shown in Table 2 below were milled using a 16 mesh sieve and mixed in a V-type mixer. The mixture was compression molded under a pressure of 60 KN with a rotary tabletting machine to prepare solid oral formulations (160 mg) containing the valsartans of Examples 1 to 3.

Preparation of solid oral formulations containing valsartan by direct compression method Constituent Content (mg) Example 1 Example 2 Example 3 Valsartan 80 (50%) 80 (50%) 80 (50%) Microcrystalline cellulose 47.5 (29.7%) 47.5 (29.7%) 47.5 (29.7%) Crospovidone 23 (14.4%) 20 (12.5%) 17 (10.6%) Hydroxypropyl cellulose 5 (3.1%) 8 (5%) 11 (6.9%) Magnesium stearate 4.5 (2.8%) 4.5 (2.8%) 4.5 (2.8%)

Comparative Example  1-2: Based on the composition ratios described in the prior art Valsartan  Of oral solid dosage form

On the basis of the composition ratios described in Korean Patent Registration No. 10-0659644 (Comparative Example 1) and Korean Patent No. 10-0618038 (Comparative Example 2), a direct compression method is used instead of the granular compression method described in the prior art To prepare solid oral formulations (Comparative Example 1 and Comparative Example 2).

Preparation of oral oral dosage forms containing valsartan based on the ingredient ratios described in the prior art Constituent Content (mg) Comparative Example 1 Comparative Example 2 Valsartan 80 (50%) 80 (40%) Microcrystalline cellulose 54 (33.8%) 10 (5%) Crospovidone 20 (12.5%) - Low-substituted hydroxypropylcellulose - 92 (46%) Aerosil 200 1.5 (0.9%) 11 (5.5%) Magnesium stearate 4.5 (2.8%) 5 (2.5%) Talc - 2 (1%)

Comparative Example  3 to 6: Using a conventional binder Valsartan  Of oral solid dosage form

Solid oral formulations (Comparative Examples 3 to 6) were prepared by the direct compression method using corn starch, hydroxyethyl cellulose, and hydroxypropyl methylcellulose known as conventional binders instead of hydroxypropyl cellulose in Example 1 .

Manufacture of Valsartan-Containing Solid Oral Formulations Substituting Hydroxypropyl Cellulose Constituent Content (mg) Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Valsartan 80 80 80 80 Microcrystalline cellulose 52.5 47.5 47.5 47.5 Crospovidone 23 23 23 23 Corn starch - 5 - - Hydroxyethyl cellulose - - 5 - Hydroxypropyl methylcellulose - - - 5 Magnesium stearate 4.5 4.5 4.5 4.5

Experimental Example  1: Hardness and Massono  Measure

In order to evaluate the binding force of the oral preparations containing valsartan of the present invention, the hardness and the degree of abrasion test were conducted to compare the binding strengths of the oral preparations containing valsartan prepared in Examples and Comparative Examples. The hardness was measured using Erweka TBH210, and the degree of scratching was tested using the Hanyoung GF7-P61 model and calculated using the method described in USP 30.

The hardness test is to physically measure the hardness of solid oral formulations. The degree of fatigue is calculated as the difference in mass before and after rotation, when a certain amount of solid dosage form is placed in a round pan and rotated at a constant number of revolutions. Generally, the degree of grinding tends to become higher as the hardness becomes higher, and the binding force of the pharmaceutical composition can be evaluated by comparing the degree of grinding under the same hardness condition. Typically, the Mason's test will follow the USP (USP) and will be calculated by the mass difference before and after spinning at 25 rpm for 4 minutes. The formula is as follows.

       The results of measurement of hardness and degree of abrasion are shown in Table 5 below.

Hardness and wear rate measurement results Hardness (N) Marson (%) Example 1 112 0.329 Example 2 108 0.109 Example 3 106 0.079 Comparative Example 1 102 0.410 Comparative Example 2 109 0.312 Comparative Example 3 108 0.547 Comparative Example 4 110 0.488 Comparative Example 5 100 0.489 Comparative Example 6 102 0.392

As shown in Table 5, Examples 1 to 3, which were prepared by using the hydroxypropyl cellulose of the present invention as a binder and produced by a direct compression method, were found to have superior scratch resistance under hardness similar to those of Comparative Examples. Especially, as the addition amount of hydroxypropyl cellulose increased, the degree of scratching was improved.

In the subsequent experiments, additional tests were conducted in Example 2, which was judged to be the optimal amount of hydroxypropylcellulose, considering the refining margins and the manufacturing cost simultaneously.

Experimental Example 2: Comparative dissolution measurement

The drug release in the comparative dissolution test is similar to that in vivo, and the drug efficacy equivalence with a commercial product can be predicted by comparing the dissolution rate at the prescribed time.

The dissolution rate was observed for 60 minutes in the above Example 2, Comparative Examples 1 to 6, and the commercial formulation according to the Method 2 of the Korean Pharmacopoeia No. 9 revision dissolution test. The eluent was 900 mL of pH 4.0 buffer solution of KFDA, the temperature of the solution was 37 ° C, and the number of revolutions of the paddle was 50 rpm. The measurement results are shown in Fig.

As shown in FIG. 1, it can be seen that the drug release pattern of Example 2 is the most similar to that of the commercially available drug. On the other hand, in the comparative examples, the drug release was markedly lower than that of the commercial product, and thus it is expected that there will be a difference in the in vivo effect compared to the preparation of the present invention.

Experimental Example 3: Stability test

The stability test was conducted according to the KFDA notification standard for the Example 2 and the commercial product, and the content of the active ingredient in each storage period was measured. The measurement results are shown in Table 6 below.

As a result of the stability test of the solid oral formulation of the present invention content(%) Subject Condition 0 months 1 month 2 months Commercial product Room temperature 101.2 103.8 99.78 Acceleration (40 ° C, RH75) - 102.2 99.94 Example 2 Room temperature 98.9 100.9 98.19 Acceleration (40 ° C, RH75) - 99.45 98.80

As shown in Table 6, it can be seen that the oral formulations of the Examples are stable to the same level as the marketed preparations.

Figure 1 shows the dissolution rate comparison results of the solid oral formulations according to the invention.

Claims (5)

40 to 60% by weight of an effective amount of valsartan or a pharmaceutically acceptable salt thereof; 25 to 35% by weight of microcrystalline cellulose; 10-15 wt% crospovidone; 2 to 3% by weight of magnesium stearate; And 3% by weight or more and less than 10% by weight of hydroxypropyl cellulose, and mixing (step 1); And Directly compressing the mixture at a pressure of 50 to 70 KN using a rotary tabletting machine to produce a solid oral formulation having a degree of maling of 0.5% or less (step 2). A method of making a valsartan-containing solid oral dosage form having a haze. delete delete delete delete

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