KR101301700B1 - Pharmaceutical composition for treating tuberculosis comprising rifampicin with improved solubility and stability and method for preparing the same - Google Patents

Abstract

PURPOSE: A pharmaceutical composition for treating tuberculosis is provided to improve solubility and stability of insoluble and unstable rifampicin by adding a non-ionic surfactant and to have stability of a formulation by avoiding direct contact with drugs. CONSTITUTION: A pharmaceutical composition for treating tuberculosis contains rifampicin and a non-ionic surfactant and is a dry granule. The pharmaceutical composition additionally contains an anti-tuberculosis drug selected among isoniazid, pyrazinamide, ethambutol hydrochloride, and a mixture thereof. Rifampicin and the anti-tuberculosis drug are manufactured in a separate granule. The non-ionic surfactant is polysorbate. A method for manufacturing the pharmaceutical composition comprises the steps of: mixing a porous excipient with a hydrophilic polymer, the non-ionic surfactant, or a mixture thereof to prepare a solid dispersion; and mixing the solid dispersion and rifampicin and granulating by a dry method.

Description

Pharmaceutical composition for Treating Tuberculosis Comprising Rifampicin with Improved Solubility and Stability and Method for Preparing the Same}

The present invention relates to a pharmaceutical composition for treating tuberculosis comprising rifampicin with improved solubility and stability, and a method for preparing the same. More specifically, the present invention relates to a pharmaceutical composition for treating tuberculosis and a method for producing the same, including the solubility and stability of rifampicin by including a surfactant.

Tuberculosis is an infectious disease that has historically been the most painful to humanity. Until recently, about 8 million tuberculosis patients worldwide each year and about 2 million people have died from tuberculosis. In Korea, tuberculosis patients were so many that they were called tuberculosis kingdom in the past, but nowadays, the number of tuberculosis patients has decreased considerably due to the economic development and the nationwide eradication of tuberculosis. But more than 30,000 new cases of TB are reported each year. Tuberculosis is the largest infectious disease that threatens public health. Looking at the age group of patients, most of them have a large number of patients, especially those in their 20s and 30s. In addition, considering the highest mortality rate from tuberculosis among OECD countries (2011 Ministry of Health and Welfare, Centers for Disease Control and Prevention), it is still considered to be a significant defect in the TB treatment system, especially primary TB drugs.

Four-component combination therapy, in which four drugs (4-FDC, Isoniazid, Rifampicin, Pyrazinamide, and Ethambutol HCl) are simultaneously administered in the initial intensive phase of tuberculosis, is a temporary blow to several sites in the TB metabolism process. It is effective in preventing treatment failure by rapidly extinguishing a large amount of Mycobacterium tuberculosis as soon as possible to shorten the treatment period and blocking proliferation of drug resistant bacteria at an early stage.

The probability that Mycobacterium tuberculosis will develop resistance to several drugs at once is multiplied by the resistance rate of each drug. The most important components of tuberculosis primary treatment, isoniazid and rifampicin, have a 10 ^-14 (10 ^-6 × 10 ^-8 ) probability of simultaneous resistance to Mycobacterium tuberculosis in tuberculosis lesions. For example, if there are 1 billion (10 ⁹ ) tuberculosis bacteria in tuberculosis lesions of tuberculosis patients, there are a probability of 10 ³ tuberculosis bacteria that are resistant to isoniazid. Therefore, when this patient is treated with isoniazid alone, most of the tuberculosis bacteria susceptible to isoniazid are killed and appear to temporarily improve, but over time, bacteria that are resistant to isoniazid continue to multiply and eventually fail.

Despite the success of most cases of isoniazid and rifampicin at the same time, tuberculosis is still widespread worldwide.Unlike most other infectious diseases, tuberculosis is a long and complex process of treatment that fails. Many drug-resistant tuberculosis is increasing.

Mycobacterium tuberculosis is characterized by a very slow proliferation rate compared to other types of bacteria as well as intermittent growth (Intermittent Growth), and their metabolic activity is very low. Since anti-tuberculosis drugs are involved in the metabolic process of Mycobacterium tuberculosis and have a bactericidal effect, they are effective only at the time of proliferation for intermittently proliferating bacteria. Therefore, in order to sterilize all of them, a long-term drug administration of 6 months or longer is required. Therefore, if you take TB drugs intermittently or stop taking TB drugs during treatment, drug-resistant bacteria multiply selectively again, resulting in drug-resistant tuberculosis (multidrug-resistant tuberculosis (MDR-TB) → wide-tolerant tuberculosis (XDR-TB) → full-tolerant tuberculosis (TDR). -TB)].

It is important to prevent refractory pulmonary tuberculosis because it is difficult to treat and diagnose, and mortality is high when progressing to MDR-TB. Therefore, it is important to prevent the transition to resistant tuberculosis during initial treatment.

In addition, the most important cause of treatment failure is judged to be due to a serious defect in the primary TB drug combination as follows, in addition to irregular anti-TB drug medications.

Rifampicin is a macrocyclic antibiotic of rifamycin produced by Streptomyces mediterranei, which has two major problems in the design of the formulation.

First, rifampicin is an unstable substance that is rapidly degraded by oxidation, hydrolysis and photo degradation (Acta Chromatographica., 2007, 18, 168-179, J. Pharm. Biomed. Anal. , 2006, 41, 1438-1441).

In addition, drug-drug interaction with isoniazid, an anti-tuberculosis drug, causes rifampicin to rapidly decompose when exposed to acidic conditions in the presence of water, leading to serious problems such as developing resistance to failure to maintain blood levels in the body. (Int. J. Tuber. Lung Dis., 2003, 7, 298-303, J. Pharm. Biomed. Anal., 2005b, 39, 892-899).

In addition, in the presence of ethambutol hydrochloride in the anti-tuberculosis drug combination component, the high-humidity ethambutol hydrochloride causes water inflow into the preparation, thereby promoting the breakdown of rifampicin in the preparation through hydrolysis or soluble isoniazid activation of rifampicin (Int. J. Tuber. , 2006, 53, 201-205, J. Pharm.Biomed.Anal., 2005b, 39, 892-899).

The decomposition process of rifampicin is described in the following Scheme 1.

[Reaction Scheme 1]

 Second, in terms of solubility, rifampicin is a chemical ionic zwitterionic structure, which has different solubility values depending on pH, and dissolves well in strong acid conditions (pH 1.0: 127.2 ± 12.20 mg / mL), and weakly acidic conditions. (pH 2.5: 3.19 ± 0.23 mg / mL, pH 5.5: 0.64 ± 0.07 mg / mL) has a sharp drop in solubility, resulting in high dietary effects, delayed Cmax time, and antituberculosis. There is a potential for problems with drug expression (Int J Tuberc Lung Dis, 2003, 7, 797-803).

U.S. Patent Publication No. 2005/0249804 discloses a stable combination formulation containing rifampicin, isoniazid, pyrazineamide and ethambutol hydrochloride, which, when mixed together, do not interact with drugs but must be wet granulated. As a disadvantage, there is a possibility of problems in stability.

U.S. Patent No. 7,195,769 is an oral pharmaceutical composition containing rifampicin and isoniazid, which releases rifampicin in the stomach and isoniazid in a delayed or extended release form, thereby preventing drug release of rifampicin and isoniazid from occurring in the same gastrointestinal tract. Disclosed is a pharmaceutical composition which improves the bioavailability of rifampicin by preventing degradation of rifampicin by isoniazid. However, there is no mention or consideration of solubility and stability issues of rifampicin alone, and the release of isoniazid is delayed or prolonged due to the possibility of delaying the expression of isoniazid, the change in gastric pH with postprandial administration and the delay of gastric emptying by food. However, it has the potential to induce drug interactions (DDI) with rifampicin.

Chinese Patent Laid-Open No. 1437946 designates a formulation such that the release of rifampicin is released below the small intestine, and drugs such as isoniazid, pyrazineamide and ethambutol hydrochloride are released in the stomach because isoniazid is rapidly degraded when coexisting with rifampicin under acidic conditions. There are problems when considering the pharmacokinetic / pharmacodynamic properties of rifampicin that is solubilized and absorbed under conditions.

Due to the above problems, the conventional rifampicin alone or one or more anti-tuberculosis pharmaceutical compositions comprising at least one antituberculosis drug composition is considered to have a limitation in the treatment of tuberculosis, and can be complemented to each other and excellent tuberculosis treatment pharmaceutical composition This is required.

Accordingly, the present inventors, while studying the solubility and stability of the tuberculosis pharmaceutical composition comprising rifampicin alone or one or more anti-tuberculosis drugs, and confirmed that the solubility and stability is improved by using a nonionic surfactant To develop a pharmaceutical composition for treating tuberculosis.

An object of the present invention is to provide a pharmaceutical composition for treating tuberculosis comprising rifampicin excellent in solubility.

Another object of the present invention is to provide a pharmaceutical composition for treating tuberculosis comprising rifampicin excellent in stability.

Another object of the present invention is to provide a pharmaceutical composition for treating tuberculosis comprising rifampicin and one or more other anti-tuberculosis drugs having excellent solubility and stability.

Still another object of the present invention is to provide a method for preparing a pharmaceutical composition for treating tuberculosis, including rifampicin having excellent solubility and stability.

The pharmaceutical composition for treating tuberculosis according to the present invention is rifampicin; And surfactants.

As the form of rifampicin, various shapes and sizes of particles, such as amorphous, amorphous-micronized, crystalline, etc. can be used. In one embodiment of the invention, the rifampicin is crystalline or amorphous.

The surfactant may be selected from ionic and nonionic surfactants. Preferably, the surfactant is a nonionic surfactant, and the nonionic surfactant is not dissociated in water, and instead of having a hydrophilic group by ionicity, water by a hydroxy group or an ethylene oxide group is used. It is surfactant which has hydrophilicity by hydrogen bond with. Polyethylene glycol derivatives (higher alcohols, ethylene oxide adducts of alkylphenols) and polyhydric alcohol derivatives (partial esters of polyhydroxy compounds such as glycerin, pentaerythritol, sorbitol, and sugar) are included. Nonionic surfactants can be selected, and the nonionic surfactants are polysorbate 20 (polyoxyethylene 20 sorbitan monolaurate) and polysorbate 40 (polyoxyethylene 40 sorbitan monopalmitate) , Polysorbate 60 (Polyoxyethylene 60 sorbitan monostearate) and Polysorbate 80 (Polyoxyethylene 80 sorbitan monooleate), etc. are suitable, considering that the rifampicin is hydrophobic, hydrophobic among the polysorbate series as a surfactant included in the solid dispersion This high polysorbate 80 (Tween 80) is most preferred, of which HLB (Hydrop) The most suitable is polysorbate 80 with a hilic lipophilic balance (15.0). In one embodiment of the invention, the nonionic surfactant is a polyethylene glycol derivative, a polyhydric alcohol derivative or a mixture thereof. In one embodiment of the invention, the polyhydric alcohol derivative is polysorbate. The content of the nonionic surfactant may be 0.1 to 40 mg per 150 mg of rifampicin, preferably 1 to 25 mg per 150 mg of rifampicin, and more preferably 5 to 20 mg per 150 mg of rifampicin. In one embodiment of the invention, the weight ratio of the rifampicin to the nonionic surfactant is 150: 0.1-40.

In one embodiment of the invention, the pharmaceutical composition further comprises a solid dispersion, some or all of the nonionic surfactant is located in the pores of the porous excipient. The porous excipient is an excipient in which a hole or a gap exists in which a surrounding medium can penetrate in a carrier, and the finer and more porous the adsorbent is, the solid dispersion has a nonionic interface with the porous excipient. It has the property of including an active agent and a hydrophilic polymer in the pores. In one embodiment of the invention, the porous excipient comprises a silicon-based compound. One of the porous excipients, silicon dioxide or a substituent series of silicon dioxide, is a white solid of a powder, and is a form in which co-melts and other pharmaceutical components dissolved in a solvent can be placed in the pores thereof. Colloidal silicone dioxide (SiO ₂ ) and magnesium aluminometasilicate (Neusilin) with a bulk density of 0.1 to 0.6 of the porous excipient itself are suitable, among which colloidal silicic acid Aerosil A-200 is the best fit. For example, the content of the porous excipient may be 0.1 to 2.0, more preferably 0.5 to 1.0, in terms of the combined weight and weight ratio of the liquid nonionic surfactant and the amount of the hydrophilic polymer added. In one embodiment of the invention, the weight ratio of the nonionic surfactant to the porous excipient is 1: 0.1-10.

In one embodiment of the invention, the pharmaceutical composition further comprises a hydrophilic polymer, some or all of the hydrophilic polymer is located in the pores of the porous excipient. One of the hydrophilic polymers, polyethylene glycol is a relatively stable, non-toxic substance having different properties according to molecular weight, and a weight average molecular weight of about 200 to 35,000 is used, and polyethylene glycol 400 (PEG 400) is a somewhat tacky transparent liquid Polyethylene glycol 1,500 (PEG 1,500) is a soft solid, and polyethylene glycol 4,000-20,000 (PEG 4,000-20,000) is a white, pale solid in the form of flakes or powders. Preferably, the hydrophilic polymer is dissolved in a co-melt and a solvent, uniformly mixed with other pharmaceutical ingredients, and then placed in a porous excipient and then powdered to maintain a solid state without being converted into a liquid form. Polyethylene glycol 3,350 (PEG 3,350), polyethylene glycol 4,000 (PEG 4,000), polyethylene glycol 6,000 (PEG 6,000), and polyethylene glycol 8,000 (PEG 8,000), with molecular weights ranging from 2,000 to 8,000, are most suitable. Suitable. In one embodiment of the invention, the hydrophilic polymer is polyethylene glycol. In one embodiment of the invention, the weight ratio of the nonionic surfactant to the hydrophilic polymer is 1: 0.1-2.0. For example, the polyethylene glycol, particularly polyethylene glycol of high molecular weight (MW: 2,000 ~ 8,000) may be 0.1 to 2.0, preferably 0.5 to 1.0 in the amount and weight ratio of polysorbate added. When the hydrophilic polymer is included in the present invention, it may help to improve the solubility of the nonionic surfactant.

In one embodiment of the invention, the pharmaceutical composition further comprises an anti-tuberculosis drug other than the rifampicin, wherein the rifampicin and the anti-tuberculosis drug are separated from each other in the composition. In one embodiment of the invention, the anti-tuberculosis drug is selected from the group consisting of isoniazid, pyrazineamide, ethambutol hydrochloride and mixtures thereof. In one embodiment of the invention, the weight ratio of the rifampicin to the anti-tuberculosis drug is 1: 0.01-50.

In one embodiment of the present invention, the pharmaceutical composition comprises an additive selected from the group consisting of binders, lubricants, disintegrants, colorants, preservatives, sweeteners, stabilizers, antibacterial agents, bulking agents, antioxidants, diluents and mixtures thereof. Additionally included.

In one embodiment of the invention, the pharmaceutical composition does not include an anionic surfactant.

Method for producing a pharmaceutical composition for treating tuberculosis according to the present invention is a mixture of a hydrophilic polymer, a nonionic surfactant or a mixture thereof and a porous excipient to mix the hydrophilic polymer, the nonionic surfactant or both in the pores of the porous excipient To prepare a solid dispersion; And mixing the solid dispersion and rifampicin to produce granules by a dry method.

Method for producing a pharmaceutical composition for treating tuberculosis according to the present invention is to place a hydrophilic polymer, a nonionic surfactant or a mixture thereof and a porous excipient to place the hydrophilic polymer, the nonionic surfactant or both in the pores of the porous excipient Making a step; Preparing a granule comprising rifampicin by a dry method; Mixing the prepared rifampicin granules and the solid dispersion.

In one embodiment of the present invention, in the preparation of the solid dispersion, a nonionic surfactant, a hydrophilic polymer or a solvent may be added to form a homogeneous phase and then placed in the pores of the porous excipient.

In one embodiment of the present invention, in the preparation of the solid dispersion, a non-ionic surfactant, a hydrophilic polymer or both of them are melted (co-melting) together to form a uniform phase by adding a solvent to the pores of the porous excipient Can be located.

In one embodiment of the invention, the method comprises the steps of preparing a granule comprising an anti-tuberculosis drug other than the rifampicin by a wet method; And mixing the solid dispersion with the rifampicin granules and the anti-tuberculosis drug granules.

In one embodiment of the invention, the method further comprises the step of tableting and coating the mixture of the solid dispersion, the rifampicin granules and the anti-tuberculosis drug granules.

The pharmaceutical composition may be prepared in the form of a powder, granules, or tablets.

The pharmaceutical composition for treating tuberculosis according to the present invention may improve the solubility and stability (gastric juice and storage) of poorly soluble and unstable rifampicin by adding a nonionic surfactant, and may include one or more antituberculous drug components other than rifampicin and rifampicin. The stability of the formulation can be further improved by avoiding direct contact between the drugs via separate granules (dry or wet).

1 is a result of solubility test according to various raw materials of rifampicin as a main component, FIG. 1A is a result of solubility test in artificial gastric juice (pH 1.2), and FIG. 1B is a result of solubility test in artificial intestinal fluid (pH 6.8).
2 is a liquid stability test result graph for the case of rifampicin alone, when isoniazid is added to rifampicin, or when isoniazid and SLS or Tween 80 are added to rifampicin.
FIG. 3 is a photograph showing a photograph of a property after 2 hours of an elution test according to a change in the amount of surfactant added to rifampicin as a main component.
Figure 4 is a photograph showing a flexible material pattern during the liquid stability test.
4a) R + H + E + Z + T
4b) R + H + E + Z + S
4c) R + H + E + Z pH 1.2 after 6 hours
5A is a test result of dissolution rate comparison between Comparative Example 2 and a commercial product.
5B is a dissolution rate comparison test result of Comparative Example 5 and a commercial product.
5C is a dissolution rate comparison test result of Example 2 and a commercial item.
Figure 6 is a dissolution rate comparison test results of the commercial product, Example 4 and Comparative Example 7, Figure 6a is the dissolution test result of rifampicin in artificial gastric juice (pH 1.2), Figure 6b is the rifampicin in artificial duodenal solution (pH 4.0) 6C is a dissolution test result of rifampicin in artificial intestinal fluid (pH 6.8), and FIG. 6D is a dissolution test result of rifampicin in water.
Figure 7 is a dissolution rate comparison test results of commercial products, Example 6 and Comparative Example 8, Figure 7a is the dissolution test results of rifampicin in artificial gastric juice (pH 1.2), Figure 7b is the rifampicin in artificial duodenal fluid (pH 4.0) 7C is a dissolution test result of rifampicin in artificial intestinal fluid (pH 6.8), and FIG. 7D is a dissolution test result of rifampicin in water.
FIG. 8 is a photograph and a table showing the results of the stability test of Example 6;
9 is a graph showing the pattern of change in the content value according to the progress of the stability test, Figure 9a is a graph evaluating the stability in long-term conditions for a period of 6 months, Figure 9b is a graph showing the stability under accelerated conditions for a period of 6 months 9C is a graph evaluating stability in harsh conditions over a period of one month.

Hereinafter, preferred embodiments of the present invention will be described in detail. The present invention is not limited to the embodiments described herein but may be embodied in other forms, and the following examples are provided for the purpose of easily explaining the present invention to those skilled in the art.

Experimental Example 1.Electron microscopy and particle size analysis of each morphology of rifampicin

Electron microscopy (SEM ™ 3000/100, HITACHI) photographic and particle size analysis (RODOS / M, SYMPATEC) tests were performed on each of the morphologies (crystalline, amorphous, and amorphous-derived) of different raw state rifampicins from different manufacturers. As a result, X ₅₀ and X appeared in each amorphous 24.84㎛, 129.64㎛ ₉₀ criteria, amorphous - are the undifferentiated showed a 7.18㎛, 23.07㎛, crystalline, according to appear in 13.96㎛, 76.46㎛, morphology Were found to have different sizes and shapes depending on the crystalline and amorphous forms.

Experimental Example 2. Solubility test of each morphology of rifampicin

Solubility tests of artificial gastric juice (pH 1.2) and artificial intestinal fluid (pH 6.8) were performed as eluents for each of the morphologies (crystalline, amorphous and amorphous-pulverized) of the raw state rifampicin. Solubility (mg / L) results were confirmed by HPLC analysis, the results are shown in FIG.

-Automatic Evaporator, USP (Paddle II), 37 ℃, 50rpm

Eluent conditions: 900 mL each pH 1.2, pH 6.8

HPLC conditions: UV 238 nm

Analytical column: C18, 250 × 4.6mm, 5㎛

-Column oven temperature: 4 ℃

[Table 1]

As shown in Table 1 and FIG. 1, rifampicin has a different solubility value depending on pH. Contrary to the literature, the solubility is decreased in pH 1.2 acidic conditions, and the solubility is high in the pH range of pH 6.8 in vivo. These results are believed to be due to the wettability of rifampicin, a poorly soluble drug, due to the shape of the raw material, as shown in Experimental Example 3 below.

Experimental Example 3. Wetting test for each morphology of rifampicin

Wetting tests of artificial gastric juice (pH 1.2) were performed for each morphology of the raw state rifampicin (crystalline, amorphous and amorphous-pulverized) as an eluent, and observed after 2 hours. As a result, it was confirmed that rifampicin was not dissolved by floating in the eluate due to the wettability of each morphology (crystalline, amorphous and amorphous- fine powder).

Experimental Example 4. Liquid Stability Test of Rifampicin

To confirm the liquid stability and drug interactions of rifampicin, content changes were measured at artificial gastric juice conditions for rifampicin alone, rifampicin + isoniazid, rifampicin + isoniazid + sodium lauryl sulfate, and rifampicin + isoniazid + polysorbate 80 combination. The results were confirmed by HPLC analysis, the results are shown in Table 2 and FIG. In addition, after adding 1 mg or 10 mg of anionic surfactant (SLS) or 10 mg or 40 mg of nonionic surfactant (polysorbate 80) to rifampicin, the appearance was observed 2 hours after the dissolution test. Is shown in FIG. 3. Also, pH 1.2 for a mixture of rifampicin (R) + isoniazid (H) + ethambutol hydrochloride (E) + pyrazineamide (Z), or a mixture of sodium lauryl sulfate (S) or polysorbate 80 (T) added thereto. After 6 hours in the eluate the components were analyzed by HPLC chromatography, the results are shown in Figures 4a, 4b and 4c.

-Automatic eluent, USP (Paddle II), 37 ℃, 50rpm

Eluent conditions: pH 1.2, 900 mL

HPLC conditions: UV 238 nm

Analytical column: C18, 250 × 4.6mm, 5㎛

-Column oven temperature: 4 ℃

[Table 2]

As shown in Table 2 and FIG. 2, rifampicin was rapidly decomposed after dissolution in liquid conditions, particularly in acidic conditions. When rifampicin and isoniazid coexist in the liquid phase, it was confirmed that the rifampicin was decomposed more quickly. In addition, sodium lauryl sulfate (SLS), an anionic surfactant, formed a hydrophobic ion conjugate with rifampicin, which drastically lowered the content of rifampicin. However, when nonionic surfactant (polysorbate 80) was added, the decomposition rate of rifampicin was significantly reduced even when coexisted with isoniazid. In addition, referring to FIG. 3, although precipitation occurred after 2 hours when 10 mg of anionic surfactant (SLS) was added to rifampicin, even when 40 mg of nonionic surfactant (polysorbate 80) was added to rifampicin, There was no precipitation after 2 hours. Also, when the nonionic surfactant (polysorbate 80) was added (Fig. 4c), the peak of rifampicin at 9.2 minutes was hardly decomposed, but when anionic surfactant (sodium lauryl sulfate) was added ( 4b) or without the addition of surfactant (FIG. 4a), the peaks of rifampicin were degraded and the area decreased, resulting in 8.2 minute, 8.6 minute, 9.5 minute, and 11 minute degradant peaks and area increase. As a result, nonionic surfactants are believed to increase the solubility of rifampicin and also contribute to the stabilization of rifampicin.

Experimental Example  5. Solid dispersion (porous excipient + Nonionic  Preparation of Surfactant + Hydrophilic Polymer)

A method of preparing a solid dispersion (in the form of a solid dispersion without a drug) including a nonionic surfactant and a hydrophilic polymer in the pores is as follows.

1. Put high molecular weight PEG into glass container, warm to about 60 ℃, and dissolve.

2. After PEG is completely dissolved, add a liquid nonionic surfactant under warming conditions, stir and mix using a mechanical stirrer.

3. Add ethanol which is a solvent to the mixture of No. 2, stir and mix using a mechanical stirrer.

4. After apologizing the porous SiO ₂ into the high speed mixer, add the mixture three times and slowly combine it. [Agitator, Chopper operation]

5. After granulation four times, dry for 8 hours in a 40 ℃ dryer.

6. After checking the drying loss, proceed to further drying or to the next process.

7. Formulate 5 dry objects using an oscillator.

Manufacturing example  1 to 4

In Preparation Example 1, 100 g of polyethylene glycol (PEG) 4,000, 100 g of polysorbate 20, 100 g of ethanol, and 100 g of colloidal silicon dioxide (SiO ₂ , Aerosil A-200) were added to a 1,000 mL container. It was prepared by. Preparation Examples 2 to 4 were prepared in the same manner as in Preparation Example 1 by the combination of the components shown in Table 3 below.

[Table 3]

The solid dispersions of Preparation Examples 1 to 4 quickly exhibited the surfactant activity when dispersed in an aqueous solution. This is believed to be due to the synergistic effect of increasing the specific surface area and the solubility of the hydrophilic polymer due to the use of the porous body.

Experimental Example  6. Preparation of Rifampicin Dry Granules

Rifampicin dry granules are prepared in the following flowchart 1.

[Flowchart 1]

How to prepare dry granules Part A

Comparative Example  1 to 6 and Example  1 to 3

In Comparative Example 1, 150 g of rifampicin (crystalline), 32 g of microcrystalline cellulose (Avicel PH 102), 8 g of carboxymethyl cellulose calcium (Ca-CMC), 8 g of talc, and 2 g of magnesium stearate (MgST) were added to a 500 mL container. , Was prepared by the method of producing dry granules, such as the flow chart 1 above. Comparative Examples 2 to 6 and Examples 1 to 3 were prepared in the same manner as in Comparative Example 1 by the combination of the components shown in Table 4 below. In addition, it observed by the electron microscope of the dry granules of Examples 1-3. In addition, the dissolution evaluation (USP, Paddle II, 50rpm, 37 ℃) for 2 hours in artificial gastric juice (pH 1.2) for the dry granules of Comparative Example 2, Comparative Example 5 and Example 2 was carried out 5a, 5b and 5c. Here, the overseas commercial products (rifampicin 150 mg, isoniazid 75 mg, pyrazineamide 400 mg, ethambutol hydrochloride 275 mg, 4-FDC) were used as a comparative group.

[Table 4]

Comparative Examples 1 to 3 showed low dissolution rates in the order of crystalline, amorphous, and amorphous-micronized according to the morphology of rifampicin in the absence of surfactant. Comparative Examples 4 to 6 is a form of adding an anionic surfactant sodium lauryl sulfate to rifampicin, early dissolution is faster than Comparative Examples 1 to 3, but over time, the main component is precipitated The leaching rate dropped sharply. In Examples 1 to 3, the dissolution rate of rifampicin was higher than that of sodium lauryl sulfate in the form of adding the solid dispersion (nonionic surfactant + polyethylene glycol + porous excipient) of Preparation Example 4 to rifampicin. Not only was this greatly improved, but the degree of degradation of rifampicin was also significantly lowered. In addition, in the absence of surfactants, the dissolution rate was poor in both the early and late stages compared to the commercially available product (4-FDC) (FIG. 5A), and when sodium lauryl sulfate was added, the dissolution rate was improved in both the early and late stages compared to the absence of the surfactant But still exhibited poor dissolution rates compared to the commercially available product (4-FDC) (FIG. 5B), and the addition of a solid dispersion comprising polysorbate 80 significantly improved both early and late compared to the commercial product (4FDC). Dissolution rate was shown (FIG. 5C).

Experimental Example  7. Preparation of granules containing anti-tuberculosis drugs other than rifampicin

The preparation method of the isoniazid granules (Preparation Example 5) and the granules (Preparation Examples 6 and 7) containing isoniazid and one or more antituberculosis drugs is as follows.

1. Add binder PVP K-30 and purified water to a glass container and dissolve completely with a mechanical stirrer.

2. Apology after mixing isoniazid alone or one anti-tuberculosis drug.

3. Mix disintegrant crospovidone CL with 2 apples.

4. Mix the diluent microcrystalline cellulose PH 101 with the third mixture.

5. Add 4 mixtures to the high speed mixer and slowly add 1 binding solution.

6. After granulation five times, dry for 15 hours in a 60 ℃ dryer.

7. After checking the drying loss, proceed to further drying or next process.

8. Formulate 7 drys using an oscillator.

Manufacturing example  5 to 7

Preparation Example 5 was prepared by the method for preparing wet granules by adding 75 g of isoniazid, 4.5 g of microcrystalline cellulose (Avicel PH 102), 1.5 g of crospovidone CL, 2.0 g of povidone (PVP) K, and 5.0 g of purified water to a 500 mL container. It was. Preparation Examples 6 and 7 were prepared in the same manner as in Preparation Example 5 by the combination of the components shown in Table 5 below.

[Table 5]

Experimental Example  8. Preparation of a combination containing anti-tuberculosis drugs other than rifampicin and rifampicin

Rifampicin and at least one anti-tuberculosis drug complex preparation containing one or more active ingredients is as follows (see flow chart 2 below).

1. Apology after mixing microcrystalline cellulose (Avicel PH 101), crospovidone CL, Ca-CMC and L-HPC LH-21.

2. Mix Rifampicin dry granules (Example 1) and wet granules containing at least one antituberculosis drug component other than rifampicin in a mixture of No. 1.

3. Apples colloidal silicon dioxide, add to mixture 2 and mix.

4. Apples MgST and stearic acid, then mix with three times the obtained product.

5. Tablet 4 obtained (pressing pressure 14 ~ 15 KP).

6. Coat five tablets of tablets.

7. Pack 6 coated tablets with primary PTP blister.

8. Pack the primary package with an aluminum pouch pillow.

[Flowchart 2]

Example  4 to 6

Example 4 is 220.0 g of Rifampicin dry granules of Example 1, 83.0 g of wet granules of Preparation Example 5, 5.8 g of microcrystalline cellulose PH 101, 5.8 g of crospovidone CL, 2.9 g of Ca-CMC, L-HPC LH-21 5.8 g, colloidal silicon dioxide 3.5 g, MgST 2. 9 g and stearic acid 2.3 g were added to prepare a preparation method shown in the flow chart 2 above. Examples 5 and 6 were prepared in the same manner as in Example 4 in combination with the components shown in Table 6.

TABLE 6

Comparative Example  7 and 8

Comparative Example 7 is 200.0 g of rifampicin dry granules (Comparative Example 4), 83.0 g of wet granules (Preparation Example 5), 5.8 g of microcrystalline cellulose PH 102, 5.8 g of crospovidone CL, 2.9 g of Ca-CMC, L- 5.8 g of HPC LH-21, 3.5 g of colloidal silicon dioxide, 2.9 g of MgST and 2.3 g of stearic acid were added to prepare the same method. Comparative Example 8 was prepared in the same manner as in Comparative Example 7, in combination of the components shown in Table 7 below.

[Table 7]

Commercially available product (4-FDC), Example 4 and Comparative Example 7, respectively, compared with the dissolution rate of rifampicin in artificial gastric juice (pH 1.2), artificial duodenal liquid (pH 4.0), artificial intestinal fluid (pH 6.8) and water, respectively. As shown in FIG. 6D, the commercial product (4-FDC), Example 6, and Comparative Example 8 respectively, dissolution rate in artificial gastric juice (pH 1.2), artificial duodenal fluid (pH 4.0), artificial intestinal fluid (pH 6.8) and water of rifampicin, respectively The comparison is shown in Figures 7a to 7d.

For the anti-tuberculosis drug combination containing the rifampicin of Examples 4 to 6, when dissolution rate was compared, it was confirmed that the dissolution rate was improved compared to Comparative Examples 7 and 8 and commercially available products as in rifampicin alone (Example 2). The degree of degradation of rifampicin was also significantly lowered. It was also confirmed that it is stable with drugs other than rifampicin.

Experimental Example  9. Stability Test

As a test conducted to confirm the stability of the formulation through the stability test (long-term / acceleration / harsh conditions), a test for evaluating the properties and content stability of the formulation according to the change over time was carried out for Example 6. For Example 6, a PTP blister packaging and a pillow packaging with an outer aluminum pouch were subjected to stability tests. Stability tests were conducted in a Stability Chamber of long term, accelerated and harsh conditions. Each test condition was carried out in a long-term test 25 ± 2 ℃ / relative humidity 60 ± 5%, accelerated test 40 ± 2 ℃ / relative humidity 75 ± 5% and harsh test 60 ± 2 ℃ / relative humidity 75 ± 5%. The stability test period was observed for 6 months in long-term and accelerated conditions and 1 month in severe conditions, and compared with the initial values. Judging criteria confirmed the change over time and the suitability of content (90.0 ~ 110.0% based on the content of the composite). The stability test results of Example 6 are shown in FIGS. 8 and 9. Overseas commercial products (rifampicin 150 mg, isoniazid 75 mg, pyrazineamide 400 mg, ethambutol hydrochloride 275 mg, 4 FDC) were used as a comparative group. The evaluation criteria of the property change is shown in Table 8 below.

[Table 8]

8 and 9, it can be seen that Example 6 is suitable for the change and content test results over time under long-term and accelerated conditions.

Claims (21)

A pharmaceutical composition for treating tuberculosis, which is a dry granule, comprising rifampicin and a nonionic surfactant,
Further comprising an antituberculosis drug selected from the group consisting of isoniazid, pyrazineamide, ethambutol hydrochloride and mixtures thereof, wherein the rifampicin and the antituberculosis drug are prepared as separate granules,
The pharmaceutical composition for treating tuberculosis, wherein the nonionic surfactant is polysorbate. delete delete delete delete The pharmaceutical composition for treating tuberculosis according to claim 1, wherein the weight ratio of rifampicin to nonionic surfactant is 150: 0.1-40. The method of claim 1, further comprising a solid dispersion, wherein the solid dispersion comprises a porous excipient, some or all of the nonionic surfactant is located within the pores of the porous excipient,
Here, the porous excipient is colloidal anhydrous silicate (Colloidal silicone dioxide, SiO ₂ ) or magnesium alumina metasilicate (Magnesium aluminometasilicate, Neusilin) pharmaceutical composition for treating tuberculosis. The pharmaceutical composition for treating tuberculosis according to claim 7, wherein the colloidal anhydrous silicic acid is colloidal anhydrous silicic acid Aerosil A-200. The pharmaceutical composition for treating tuberculosis according to claim 7, wherein the weight ratio of the nonionic surfactant to the porous excipient is 1: 0.1-10. The method of claim 7, wherein the solid dispersion comprises a hydrophilic polymer, a part or all of the hydrophilic polymer is located in the pores of the porous excipient,
Here, the pharmaceutical composition for treating tuberculosis wherein the hydrophilic polymer is polyethylene glycol. delete The pharmaceutical composition for treating tuberculosis according to claim 10, wherein the weight ratio of the nonionic surfactant to the hydrophilic polymer is 1: 0.1-2.0. delete delete The pharmaceutical composition for treating tuberculosis according to claim 1, wherein the weight ratio of rifampicin to anti-tuberculosis drug is 1: 0.01-50.  2. The treatment of tuberculosis according to claim 1, further comprising an additive selected from the group consisting of binders, glidants, disintegrants, colorants, preservatives, sweeteners, stabilizers, antibacterial agents, bulking agents, antioxidants, diluents and mixtures thereof. Pharmaceutical composition for. delete Mixing a hydrophilic polymer, a nonionic surfactant or a mixture thereof and a porous excipient to prepare a solid dispersion by mixing the hydrophilic polymer, the nonionic surfactant, or both in the pores of the porous excipient; And
Method of producing a pharmaceutical composition for treating tuberculosis comprising the step of preparing the granules by a dry method after mixing the solid dispersion and rifampicin. Mixing a hydrophilic polymer, a nonionic surfactant or a mixture thereof with a porous excipient to place the hydrophilic polymer, the nonionic surfactant or both in the pores of the porous excipient to prepare a solid dispersion;
Preparing a granule comprising rifampicin by a dry method; And
Method for producing a pharmaceutical composition for treating tuberculosis comprising the step of mixing the prepared rifampicin granules and solid dispersion. 19. The method of claim 18, further comprising the steps of: preparing a granule comprising an anti-tuberculosis drug other than the rifampicin by a wet method; And
Mixing the solid dispersion and the rifampicin and the anti-tuberculosis drug granules further comprising the step of producing a pharmaceutical composition for treating tuberculosis. The method of claim 20, further comprising the step of tableting and coating the mixture of the solid dispersion and the rifampicin and the mixture of the anti-tuberculosis drug granules.

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