KR101118794B1 - Pharmaceutical composition containing bisphosphonate - Google Patents

Abstract

The present invention provides a pharmaceutical composition comprising a bisphosphonate, a pH-sensitive polymer material, a bubble forming agent and a buffer having an osteoporosis treatment effect. The composition of the present invention does not need to take a large amount of water at the time of administration, and also has sufficient buffering ability to maintain the pH in the stomach after taking the drug after taking the drug by preventing esophageal irritation due to gaseous reflux There is no need to maintain a separate standing posture. In addition, in some patients with too low gastric acid, even if the pH in the stomach is lowered to 3.5 or less, floating swelling rafts can be formed to prevent esophageal irritation due to gaseous reflux, so that patients taking bisphosphonate drugs for a long period of time. It greatly improves the convenience of medication, and has a foaming effect in two stages.

Bisphosphonates, Rafts

Description

Pharmaceutical composition containing bisphosphonate

The present invention relates to pharmaceutical compositions containing bisphosphonates, which are therapeutic agents for osteoporosis.

Osteoporosis refers to a condition in which bone fracture is high due to weakened bone strength due to the amount or quality of bone, and is caused by genetic factors, early menopause, steroids, and other drugs.

Drugs used for the treatment of osteoporosis include calcium, vitamin D, female hormone preparations, bisphosphonate preparations and parathyroid hormones. Among these, bisphosphonate preparations are the most widely used drugs for treating osteoporosis. By preventing the reabsorption of bone mediated by), it prevents the escape of calcium from the bone. Representative bisphosphonates for the treatment of osteoporosis include alendronate, risedronate, zoleronate, ibandronate, minodronate, and these drugs are acid or metal salts. Used in the form of

Most formulations containing bisphosphonates administered orally are administered in the form of solids, and when administered to the esophagus, there is a risk of causing inflammation or ulceration by local irritation. It is intended to be taken with 240 ml of large amounts of water. In addition, to prevent esophageal irritation from gastric reflux even after taking it is to maintain a standing posture for about 30 minutes to 1 hour. Therefore, such a method not only greatly reduces the compliance of the medications for patients who need to take the drug for a long time, but also a serious problem that is urgently improved in view of the fact that most patients receiving bisphosphonate drugs are old and weak in gastrointestinal function. It can be said.

Stimulation of bisphosphonates in the gastrointestinal mucosa has not been shown to be associated with changes in mucosal prostaglandin levels, which has not been shown to be systemic, such as NSAIDs (Digestive and Liver Disease, 35, 2003). , 67-70). In particular, when intravenous bisphosphonate is administered, the irritation of gastrointestinal mucosa is not expressed, which means that the drug acts directly on the gastrointestinal mucosa and shows stimulating properties.

Alendronate, a representative drug of bisphosphonates, is present in the form of a nonionic acid (Acid) under strongly acidic conditions of pH 2 and below, and is much more irritating than the sodium salt of allendronate, which results in direct irritation to the gastrointestinal mucosa. It is known to cause oxidative damage with neutrophil infiltration into tissues. Due to this characteristic, when oral administration of a formulation containing alendronate results in a low pH in the stomach, most of allendronate is present in a nonionic form, which causes severe irritation of the esophagus upon gastric reflux (Prostaglandins, Leukotriens, Essential fatty acids, 72, 2005, 1-11).

The pH-dependent irritation of bisphosphonates on the gastrointestinal mucosa was found by the administration of various pH solutions containing allendronate and risedronate in esophageal perfusion models using beagle dogs. A solution containing no pH at all pH values containing alendronate or risedronate and a solution without pH were perfused through the esophagus of a beagle dog for a period of time, and then compared with irritation. After perfusion, some cell infiltration was expressed in the mucosal tissue, but more severe mucosal damage occurred such as esophagitis or ulcer during perfusion of the buffer containing drug. On the other hand, administration of solutions at pH 3.5 and 5 showed no esophageal irritation at all, regardless of drug content. As such, the irritation properties of the bisphosphonate-containing solution vary greatly depending on pH, and it can be seen that mucosal irritation is severe especially under strong acid conditions of pH 2 or below (Digestive disease and sciences, 43, 9, 1998, 1998-2002).

Bisphosphonate formulation patents to improve this problem are as follows.

Korean Patent Publication No. 10-0372966 discloses the use of an alendronate liquid formulation for treating or preventing bone loss in a patient who is difficult to swallow as a liquid alendronate formulation for oral administration. The composition is characterized in that the pH is maintained in the range of 2 to 8 and comprises a complexing agent to prevent precipitation in aqueous solution. However, in the present invention, the buffer is not used for the purpose of preventing mucosal irritation in the stomach of bisphosphonate but is used for the purpose of keeping the pH of the formulation constant in terms of formulation. There is no mention of possible buffering capacity and therefore it is difficult to determine that the patient can control the pH in the stomach when the composition is taken and due to gastric reflux when the pH of the preparation is lower than 3.5 due to insufficient buffering capacity of the preparation. There is virtually no mention of how to prevent possible stimuli.

Korean Patent Laid-Open Publication No. 10-2000-0048829 has the advantage of further relieving heartburn symptoms with alendronate for the purpose of preventing heartburn in patients with symptoms of reflux esophagitis among patients in need of alendronate. Liquid alendronate formulations are disclosed. In the present invention, apart from the irritation of the alendronate, the present invention may be different from the present invention in that it is intended to prevent heartburn by administering an allandronate liquid having a buffering capacity to osteoporosis patients having heartburn symptoms due to gastric reflux. This composition also does not disclose a method that can prevent the irritation that can be caused by the alendronate when gastric reflux when the pH of the content is less than 3.5 because the buffer capacity is not sufficient in the stomach.

U.S. Patent No. 5853759 discloses a foam formulation containing an alendronate and this composition is also made for the purpose of improving the ease of administration when administering to elderly patients. However, this also does not mention the buffering capacity of the dosage solution, nor does it disclose a protection against irritation that may occur when the buffering capacity is insufficient.

U.S. Patent No. US Pat. It is not disclosed how to prevent the stimulation that may occur by.

Korean Patent Publication No. 10-2008-0030643 discloses a composition for the treatment of reflux esophagitis, gastritis or peptic ulcer as a particulate composition composed of alginate and / or alginic acid, bicarbonate and / or carbonate, organic acid, and flocculant. The composition of the present invention is characterized in that it further contains a drug for treating gastrointestinal diseases, but does not disclose a composition containing bisphosphonate, which is a therapeutic agent for osteoporosis, which is not intended to treat gastrointestinal diseases, and further, uses for preventing gastrointestinal mucosal irritation of bisphosphonates. It is also not disclosed. However, since this composition does not contain a left pill, it does not have the function of adjusting the pH in the stomach after taking it, and also contains about 33-35% of sodium alginate in the unit dosage form so that it does not disintegrate when prepared in the form of tablets. There is a problem, which limits the formulation to the form of a powder. In addition, the composition is intended to be taken directly in the form of a powder, in which case there is a fundamental problem that the raft gel cannot be formed because sodium alginate in solid form is directly contacted with gastric acid.

Meanwhile, the floating swelling type raft (Raft) refers to a swellable gel that has a characteristic of floating like a raft in the stomach when taken. A representative commercial product is Geviscon® (Liquid Gaviscon® GSK). Gebiscone contains a large amount of divalent metal ions such as aluminum or magnesium in addition to alginic acid as a antacid, and when bisphosphonates are simply included in such a raft gel composition, polyvalent cations such as aluminum, calcium, and magnesium are contained in bisphosphonates. The formation of complexes results in serious problems that inhibit the absorption of bisphosphonates in the body.

Gebiscones also contain a large amount of sodium alginate, which does not disintegrate when prepared in tablet form, which limits the formulation to suspension form and limits the preparation of effervescent tablets or foam granules.

The inventors of the present invention provide a patient with sufficient buffering capacity to maintain the pH of the gastric contents above 3.5 for the purpose of solving the problem of the conventional bisphosphonate-containing formulations, which are to be taken with a large amount of water and maintain a standing posture for a long time after the administration. Even if the pH in the stomach decreases to 3.5 or less, it immediately forms a floating swelling type raft to prevent esophageal irritation due to gaseous reflux, and can be taken as a small solution / suspension or dissolved / suspended in a small amount of water. In addition, the present invention has completed the invention of a bisphosphonate-containing pH-sensitive floating swelling Raft pharmaceutical composition that does not require a separate standing posture.

The present invention provides a pH-sensitive floating swelling Raft pharmaceutical composition containing bisphosphonate, a therapeutic agent for osteoporosis.

The present invention provides a pharmaceutical composition comprising a bisphosphonate, a pH sensitive polymer material, a bubble former and a buffer.

Hereinafter, the present invention will be described in detail.

Bisphosphonates according to the present invention are used for the purpose of treating osteoporosis and are drugs of bisphosphonates including bisphosphonate structures in the drug, such as, for example, alendronate, risedronate, zledronate, ibandro Ibandronate, minodronate and the like, and these drugs are used in the form of acid or metal salts and anhydrides or hydrates.

The pH-sensitive polymer material contained in the composition of the present invention means a polymer material that forms a gel under a condition of pH 3.5 or less. For example, alginic acid or a metal salt thereof, pectin, and the like may be used.

Alginic acid is a viscous natural polysaccharide obtained from natural algae and consists of carbon, hydrogen and oxygen, and has a molecular weight ranging from 10,000 to 600,000, and is a continuous chain of (1, 4) β-Mannuronate and (1, 4) aL-Gluronate. It has different physical properties according to the characteristics of their arrangement. Metal salts of alginic acid, in particular sodium alginate, are soluble in water and have the characteristic of forming gels selectively at pH 3.5 or below, depending on the pH and of physical properties. Sodium alginate can have a variety of viscosities in aqueous solution. For example, sodium alginate supplied under the trade name Protanal from FMC Biopolymer, depending on the viscosity, LFR5 / 60 (300-700 mPa.s, 10% aqueous solution), LF 120 M (70-150 mPa.s, 1% aqueous solution), LF 240 D (70-200 mPa.s, 1% aqueous solution), LF 200 M (200-400 mPa.s, 1% aqueous solution), HF 120 RBS (600 1000 mPa.s, 1% aqueous solution) and the like can be supplied. When sodium alginate is used as a polymer for forming a pH-sensitive gel of the composition of the present invention, when a large amount of high viscosity sodium alginate is used, it is difficult to form floating swelling-type rafts in response to pH in the stomach and at the same time It may cause harm or taste. Thus, the viscosity of the present invention in the effervescent tablet or expanded granule composition in 120 ml of water or the viscosity of the solution / suspension was 26 cP measured at a rotational speed of 50 rpm using the Brookfield type viscometer spindle 2 It is preferable to select the kind and amount of sodium alginate so as to show the following.

Pectin is a natural complex polysaccharide present in the cell walls of plants (1, 4) partially substituted (1, 2) LR hamnose, D-Galactose, D-Arabinose, D-Xylose in the linear chain of α-D- Galacturonic acid It has a structure in the form of a compound and has a molecular weight ranging from 60 to 130,000. Pectin is classified according to the degree of methylation of the carboxyl group of Galacturonic acid by esterification reaction, and in case of pectin supplied under the trade name Genu Pectin by CPKELCO, Type LM 101 AS (35% esterification), LM 102 AS (30% esterification), LM 104 AS (27% esterification) and the like can be supplied. When pectin is used as a polymer material for forming a pH-sensitive gel of the composition of the present invention, the lower the degree of esterification, the better the gel formation ability.

The foaming agent according to the present invention generates carbon dioxide bubbles in the stomach when the composition of the present invention is directly taken in the form of a solution or suspension, or dissolved or suspended in water, and then the bubbles generated are pH sensitive. When the gel-forming polymer forms the swelling gel under acidic conditions, it is trapped inside the gel to give the gel a floating property. As a result, the gel floats on the upper surface of the gastric juice to form a raft-type floating swelling gel. To form.

The bubble forming agent contained in the composition of the present invention may be in the form of a bicarbonate metal salt or a metal salt of carbonate alone or in combination with an organic acid, more preferably a combination of a metal salt of an organic bicarbonate and an organic acid. . Metal salts of bicarbonate will generate bubbles at acidic pH, and bubble formation can be further promoted by combination with organic acids.

As the metal salt of bicarbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like can be used, and carbonate metal salts include sodium carbonate and potassium carbonate.

Citric acid, succinic acid, malic acid, tartaric acid, fumaric acid, adipic acid, etc. may be used as the organic acid. The bubble forming agent is more preferably a combination of sodium bicarbonate and citric acid.

When the composition according to the invention is in the form of effervescent tablets or effervescent granules, bubbles are generated at each step when dissolved or suspended in water and when taken and then reacted with pH in the stomach to form a raft gel. For example, when sodium bicarbonate and citric acid are used as bubble forming agents, a preferable weight ratio of sodium bicarbonate and citric acid to be able to generate a sufficient amount of bubbles in each step is 1: 0.01 to 0.99, more preferably. Is 1: 0.1 to 0.75. If the ratio of citric acid is too high, the total amount of sodium bicarbonate in the composition is used to generate air bubbles when the initial effervescent tablet is dissolved or suspended in water. Problems that do not occur occur. On the other hand, if the ratio of citric acid to sodium bicarbonate is too low, a sufficient amount of bubbles are not generated when dissolving or suspending effervescent tablets in water, causing disintegration or delayed disintegration time.

In addition, the buffer according to the present invention functions to maintain the pH of the gastric contents above a certain level when the composition of the present invention is directly taken in the form of a solution or suspension, dissolved or suspended in water, and then taken. Is characterized by having a buffering ability to adjust to pH 3.5 or more is known that the mucosal irritant of bisphosphonates do not appear. The buffering capacity of the compositions of the present invention generally provides a constant level of gastric pH in the gastric pH of many patients taking bisphosphonates by setting the composition and proportion of the buffer to meet the in vitro buffering capacity evaluation criteria of the antacid. Is to be maintained at 3.5 or more, but it is characterized by the fact that the gastric acidity is extremely low to block mucosal irritation due to gas flow reflux through the formation of a pH-sensitive Raft gel for patients who do not pH adjustment. The buffer of the present invention was dissolved in 120 ml of water by dispersing the pharmaceutical composition of the present invention, and then each test solution was added to 37 ° C and 250 ml of 0.02 N hydrochloric acid solution, and the 0.1 N hydrochloric acid solution was added at a rate of 2 ml / min. It is desirable to be able to maintain at least 8 meq when measuring the amount of 0.1 N hydrochloric acid used until the pH of the solution drops from 4.5 to 2.5 with addition.

As the buffer included in the composition of the present invention, an organic acid and its base may be used, for example, citric acid, succinic acid, malic acid, acetic acid, malic acid and its base. It is preferable to use citric acid anhydride or its hydrate together with its base base as a buffer, more preferably citric acid and sodium citrate.

In addition, the pharmaceutical composition according to the present invention may be prepared in the form of a dosage form of a solution or suspension for administration to the human body, or in the form of a dosage form such as effervescent tablets or effervescent granules, which is taken by dissolution or suspension in water. . When the pharmaceutical composition according to the present invention is in the form of a solution or a suspension, it may be prepared by further using a solvent, a sweetener, a flavoring agent, a coloring agent, a stabilizer, and a preservative, and the manufacturing method is a general method of preparing a solution or suspension. It can be prepared through.

When the composition of the present invention is prepared in the form of a form in which it is dissolved or suspended in water, for example in the form of effervescent tablets, excipients, sweeteners, flavoring agents, colorants, binders, disintegrants, glidants and the like can be prepared. However, the effervescent tablet according to the present invention should be quickly disintegrated within 3 minutes, preferably within 2 minutes when added to water, the buffer capacity to adjust the pH in the stomach even after disintegrating dissolved or suspended in water And under a condition of pH 3.5 or less, it is desirable to be able to quickly react to form a raft (Raft) gel.

Further examples of preferred bisphosphonate-containing pharmaceutical compositions of the present invention are as follows:

1. Bisphosphonates are sodium risedronate; the pH sensitive polymeric material is sodium alginate; Bubble formers are sodium bicarbonate and citric acid; The buffer is an effervescent tablet or expanded granule composition, wherein the buffer is citric acid and sodium citrate.

2. The bisphosphonate is sodium ibandronate; the pH sensitive polymeric material is sodium alginate; Bubble formers are sodium bicarbonate and citric acid; The buffer is an effervescent tablet or expanded granule composition, wherein the buffer is citric acid and sodium citrate.

3. The bisphosphonate is sodium alendronate; the pH sensitive polymeric material is sodium alginate; Bubble formers are sodium bicarbonate and citric acid; The buffer is an effervescent tablet or expanded granule composition, wherein the buffer is citric acid and sodium citrate.

4. The bisphosphonate is sodium risedronate; the pH sensitive polymeric material is pectin; Bubble formers are sodium bicarbonate and citric acid; The buffer is an effervescent tablet or expanded granule composition, wherein the buffer is citric acid and sodium citrate.

5. Bisphosphonates are sodium ibandronate; the pH sensitive polymeric material is pectin; Bubble formers are sodium bicarbonate and citric acid; The buffer is an effervescent tablet or expanded granule composition, wherein the buffer is citric acid and sodium citrate.

6. The bisphosphonate is sodium alendronate; the pH sensitive polymeric material is pectin; Bubble formers are sodium bicarbonate and citric acid; The buffer is an effervescent tablet or expanded granule composition, wherein the buffer is citric acid and sodium citrate.

The composition of the present invention does not need to take a large amount of water at the time of administration, and also has sufficient buffering ability to maintain the pH in the stomach after taking the drug after taking the drug by preventing esophageal irritation due to gaseous reflux There is no need to maintain a separate standing posture. In addition, in some patients with too low gastric acid, even if the pH in the stomach is lowered to 3.5 or less, floating swelling rafts can be formed to prevent esophageal irritation due to gaseous reflux, so that patients taking bisphosphonate drugs for a long period of time. It greatly improves the convenience of medication, and has a foaming effect in two stages.

Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the examples.

Example A Preparation of pH Sensitive Raft Foamed Tablets Containing Bisphosphonates

a. Preparation of effervescent tablet according to the type and amount of pH-sensitive polymer material

As shown in [Table 1] and [Table 2], the type and amount of the pH-sensitive polymer material are differently selected and mixed with sodium risedronic acid, bubble forming agent (citric acid), and other excipients (mannitol) at room temperature, and the binder solution. (PVP k30 solution) was added and granulated using a high speed mixer (Diosna, Pharma mixer 1/6), followed by drying and sizing to prepare granules, which contained a foaming agent (sodium bicarbonate) and a buffer (sodium citrate). , Citric acid), an appropriate amount of lubricant (PEG 6000), flavoring agent (pepamine) and sweetening agent (sucralose) were added and compressed. In Comparative Example 1, a foamed tablet containing no polymer for forming a pH sensitive gel was prepared.

[Table 1]

TABLE 2

b. Preparation of effervescent tablets with different capacity of bubble former and buffer

As shown in [Table 3], citric acid was used as sodium citrate, pH-sensitive polymer material (sodium alginate) by using different ratios of sodium bicarbonate to citric acid used as a bubble forming agent and sodium citrate to citric acid used as a buffer. The granules were prepared by mixing with other excipients (mannitol), adding a binder solution (PVP k30 solution), and then using a high speed mixer, followed by drying and sizing. A foaming agent (sodium bicarbonate), a buffer (sodium citrate, citric acid), an appropriate amount of lubricant (PEG 6000), a flavoring agent (pepamine), and a sweetening agent (sucralose) were added thereto. In Comparative Examples 2, 3 and 4, effervescent tablets were prepared which did not contain sodium bicarbonate or citric acid as the foaming agent and sodium citrate as the buffer, respectively.

[Table 3]

c. Manufacture of various bisphosphonate-containing effervescent tablets

Example 25 In Example 2 of the above [Table 1], sodium ibandronate-containing effervescent tablets were prepared in the same manner as in Example 2, except that 150 mg of sodium ibandronate was added instead of 150 mg of sodium riseron. Was prepared.

Example 26 In Example 2 of the above [Table 1], sodium ibandronate-containing effervescent tablets were prepared in the same manner as in Example 2, except that 70 mg of allentroate was added instead of 150 mg of sodium riseronate. Prepared.

Example B Preparation of pH-Sensitive Raft Granules Containing Bisphosphonates

Various bisphosphonates (sodium dredron, sodium ibandronate, sodium alendronate), pH-sensitive polymer materials (sodium alginate, pectin), foaming agents (citric acid), and other excipients (mannitol) as shown in Table 4 below. Were mixed, granulated using a high speed mixer with the addition of binder (PVP k30), and then dried and granulated to prepare granules. A bubble forming agent (sodium bicarbonate), a buffer (sodium citrate), a flavoring agent (pepamine), and a sweetening agent (sucralose) were added thereto and mixed.

[Table 4]

Example C Preparation of pH-Sensitive Raft Solution / Suspension Containing Bisphosphonates Bisphosphonates (sodium riseronate, sodium ibandronate, sodium alendronate), pH-sensitive polymer materials as shown in Table 5 below. (Sodium alginate, pectin), bubble-forming agent (sodium bicarbonate, citric acid), buffer (citric acid, sodium citrate), other excipients (sucralose, peppermint, paraoxybenzoate, methyl paraoxybenzoate) in dissolved water at room temperature Next, the solution was prepared by filtration and autoclaving.

TABLE 5

Experimental Example 1 Disintegration Test of Foamed Tablets

1. Test Method

EXAMPLES The foamed tablets of Compositions 1 to 22, 25 and 26 and Comparative Examples 2 and 3 were placed in a beaker containing 120 ml of water, and then foamed, and the disintegration and time of tablet disintegration were visually measured. After dispersing and dissolving the effervescent tablets of the following Examples and Comparative Examples in 120 ml of water, and using a Brookfield type viscometer to measure the value when rotating the spindle No. 2 at 50 rpm.

2. Test result

TABLE 6

TABLE 7

[Table 8]

As described in [Table 6] to [Table 8], in the case of the foamed tablets of most examples, disintegration was completed within approximately 3 minutes with foaming, and the lower the viscosity of sodium alginate and the smaller the content in the unit dosage form, the faster disintegration occurred. The trend was shown.

In particular, disintegration was completed within 3 minutes when the example composition was dissolved in 120 ml of water and measured at 26 rpm by rotating spindle 2 at 50 rpm using a Brookfield type viscometer. For Examples 10-18 containing pectin up to 35% esterification, disintegration was completed within approximately 2 minutes regardless of the content in the unit dosage form.

As a result of evaluating Examples 2, 19 and 20, as the amount of sodium bicarbonate was increased, the disintegration rate was increased. As a result of evaluating Examples 2, 21 and 22, the disintegration rate was increased as the amount of citric acid was increased. Was found to be faster. However, foaming did not occur in Comparative Examples 2 and 3 containing no sodium bicarbonate or citric acid, and thus did not disintegrate.

In addition, it was confirmed from the evaluation results of Examples 2, 25, and 26 that the disintegration time according to the type of bisphosphonate does not differ when the sodium bicarbonate and citric acid are included in the foaming ability.

Experimental Example 2 Buffer Capacity Test

1. Test Method

An improved in vitro method for the evaluation of antacids with in vivo relevance, European Journal of pharmaceutics and Biopharmaceutics 53 (2002) 217-225) were evaluated as follows.

Examples 2, 21 to 23, 25, 26 and Comparative Examples 3 and 4 were dispersed and dissolved in 120 ml of water, and each test solution was added to 37 ° C. and 250 ml of 0.02 N hydrochloric acid solution for 4 minutes and 20 minutes. The pH was then measured and the amount of 0.1N hydrochloric acid used was measured until the pH of the solution dropped to 2.5 while adding 0.1N hydrochloric acid solution at a rate of 2 ml / min. Evaluation of the buffer capacity was evaluated by the following four parameters, the calculation of each parameter is shown in the following [Table 9].

TABLE 9 Buffer Performance Evaluation Parameters

2. Test result

TABLE 10

As described in Table 10 above, in Comparative Examples 3 and 4 in which sodium citrate or citric acid was not included as a buffer, buffer capacity was not secured. However, in Examples 2, 21, 23, 25, and 26, all evaluation parameters were met, and the minimum amount of sodium citrate used to ensure buffering capacity increased when the amount of citric acid contained in the composition decreased. Indicated.

Experimental Example 3 Raft Gel Formation Ability Test

1. Test Method

Examples 1 to 22 and 24 to 26, Comparative Examples 1 and 2, respectively, were added to 120 ml of water to dissolve, and then to 50 ml of artificial gastric juice having two concentrations of hydrochloric acid, and then visually evaluated gel formation. There are two levels of gastric juice: 0.1N and 1N.

2. Test result

TABLE 11

[Table 12]

TABLE 13

As shown in Comparative Examples 1 and 2 of Tables 11 to 13, no raft gel was formed in the foamed tablet containing no pH sensitive polymer material or bubble-forming agent regardless of the concentration of the gastric juice. On the other hand, in Examples 1 to 22, 25, and 26 containing the pH polymer material and the bubble-forming agent, the pH of the test solution was added to 50 ml of 0.1 N artificial gastric fluid when each test solution was dispersed and dissolved in 120 ml of water. About 5.3 to 5.6, no raft gel was formed, but when each test solution was added to 50 ml of 1 N artificial gastric juice, the pH of the test solution was 0.8 to 1.0, and a floating swelling raft gel was formed immediately. Particularly, in the case of containing sodium alginate as the pH sensitive polymer, the higher the viscosity of alginic acid and the higher the content in the unit dosage form, the higher the thickness and volume of the gel.The example composition was dissolved in 120 ml of water and Brookfield Raft gels formed well at 26 cps or less as measured by rotating spindle 2 at 50 rpm using a type viscometer. In addition, in Examples 10 to 18, which contained less than 35% of esterification degree, the raft gel was formed in response to the pH regardless of the content in the unit dosage form.

In addition, the effervescent tablet of the present invention exhibited bubble formation in two stages when the ratio of sodium bicarbonate to citric acid exceeds 1, and this composition ratio showed a certain aspect regardless of the type of bisphosphonate.

Experimental Example 4 Evaluation of Gel Formation and Release Characteristics in Various In vitro Conditions

1. Test Method

The test solution obtained by dissolving the foamed tablets of Examples 2 and 17 and the foamed granules of Example compositions 27 and 30, respectively, in 120 ml of water was added to 50 ml of various types of artificial gastric juice, and then visually examined with time for the formation of raft gel. When the gel was formed by evaluating the drug concentration in the solution, the drug release pattern from the gel was compared with the solution. The composition of the gastric juice used in the test is as follows.

[Table 14] Composition of artificial gastric juice

Evaluation of drug release was tested by the following method using high performance liquid chromatography. Example Test solution 2, 17, 27, 30 dissolved in water was added to 50 ml of artificial gastric juice, 1 ml of the test solution at the bottom of the beaker at 5, 10, 15, 30, 60 minutes and filtered, and then After dilution with distilled water, it was used as a sample solution. 150 mg of sodium risedronate standard (Fleming) was taken, dissolved and diluted in 170 ml of tertiary distilled water to obtain a standard solution. The release rate was calculated by analysis using liquid chromatography under the following conditions with the sample solution and the standard solution.

[Liquid Chromatographic Analysis Conditions]

Column: IonPac® AG7 (10 um, 4 X 50 mm)

Detection wavelength: 263 nm

Mobile phase: Dissolve 1.8 g of ethylenediaminetetraacetic dihydrogen dihydrate dihydrate in 1 L of water and adjust to pH 9.5 ± 0.1 with 1 mol / L sodium hydroxide solution.

Flow rate: 0.8 ml / min

-Sample injection volume: 20 ul

-Emission rate formula

2. Test result

The foamed tablets of Examples 2 and 17 and the foamed granules of Examples 27 and 30 were rapidly dissolved with foaming in 120 ml of water, and raft gel formation behavior when the formed solution was added to 50 ml of various artificial gastric fluids was as follows. It was like

TABLE 15

As shown in [Table 15], when the composition solution was added to 50 ml of various gastric juices, raft gel was formed when the pH of the test solution was lower than 3.5, and the drug was released into the mixed solution regardless of the raft gel formation. The amount of was constant.

1 to 22 are photographs of raft gel formation at 0.1 N and 1 N HCl concentrations of Examples 1 to 22, respectively.

23 to 27 are raft gel formation evaluation photographs at 0.1N and 1N HCl concentrations of Examples 24, 25 and 26, and Comparative Examples 1 and 2;

28 to 31 are photographs of raft gel formation evaluation in various artificial gastric juices of Examples 2, 17, 27, and 30.

32 to 35 graphically show the dissolution rate evaluation results in various artificial gastric fluids of Examples 2, 17, 27 and 30.

Claims (23)

A pharmaceutical composition for treating osteoporosis comprising bisphosphonates, pH sensitive polymer materials, bubble formers and buffers. The pharmaceutical composition for treating osteoporosis according to claim 1, wherein the pH-sensitive polymer material is a polymer material that forms a gel at a pH of 3.5 or less. The method of claim 2, wherein the pH sensitive polymeric material is such that the composition has a viscosity of 26 cP or less when dissolved in 120 ml of water and measured at a rotational speed of 50 rpm using a Brookfield type viscometer spindle 2. Pharmaceutical composition for treating osteoporosis. The pharmaceutical composition for treating osteoporosis according to claim 3, wherein the pH-sensitive polymer material is alginic acid or a metal salt thereof. The pharmaceutical composition for treating osteoporosis according to claim 4, wherein the pH-sensitive polymer material is sodium alginate. The pharmaceutical composition for treating osteoporosis according to claim 2, wherein the pH-sensitive polymer material is pectin. The pharmaceutical composition for treating osteoporosis according to claim 6, wherein the pectin has a methylation degree of 35% or less due to esterification of a carboxyl group. The pharmaceutical composition for treating osteoporosis according to any one of claims 1 to 7, wherein the bisphosphonate is an acid of alendronate, risedronate, ibandronate, a metal salt thereof, an anhydride or a hydrate thereof. The pharmaceutical composition for treating osteoporosis according to claim 1, wherein the foam forming agent is a bicarbonate or a metal salt of carbonate alone or in combination with an organic acid. The pharmaceutical composition for treating osteoporosis according to claim 9, wherein the bubble forming agent is a bicarbonate metal salt and an organic acid. The pharmaceutical composition for treating osteoporosis according to claim 10, wherein the weight ratio of the bicarbonate metal salt and the organic acid is 1: 0.1 to 0.75. The pharmaceutical composition for treating osteoporosis according to claim 9, wherein the organic acid is citric acid and the carbonate metal salt is sodium bicarbonate. The pharmaceutical composition of claim 1, wherein the buffer maintains the pH of the pharmaceutical composition at about 3.5 or higher. 14. The buffer according to claim 13, wherein the buffer is dispersed and dissolved in 120 ml of water, and then each test solution is added to 37 ° C, 250 ml of 0.02 N hydrochloric acid solution, and then 0.1 N hydrochloric acid solution is added at a rate of 2 ml / min. The pharmaceutical composition for treating osteoporosis is selected to maintain at least 8 meq when measuring the amount of 0.1N hydrochloric acid used until the pH of the solution falls from 4.5 to 2.5. The pharmaceutical composition for treating osteoporosis according to claim 13, wherein the buffer is citric acid and sodium citrate. The pharmaceutical composition for treating osteoporosis according to claim 1, wherein the pharmaceutical composition is a solution, suspension, effervescent tablet or effervescent granule. The method of claim 1, wherein the bisphosphonate is sodium risedronate; the pH sensitive polymeric material is sodium alginate; Bubble formers are sodium bicarbonate and citric acid; The buffer is a pharmaceutical composition for treating osteoporosis, which is effervescent tablets or effervescent granules are citric acid and sodium citrate. The method of claim 1, wherein the bisphosphonate is sodium ibandronate; the pH sensitive polymeric material is sodium alginate; Bubble formers are sodium bicarbonate and citric acid; The buffer is a pharmaceutical composition for treating osteoporosis, which is effervescent tablets or effervescent granules are citric acid and sodium citrate. The method of claim 1, wherein the bisphosphonate is sodium alendronate; the pH sensitive polymeric material is sodium alginate; Bubble formers are sodium bicarbonate and citric acid; The buffer is a pharmaceutical composition for treating osteoporosis, which is effervescent tablets or effervescent granules are citric acid and sodium citrate. The osteoporosis according to any one of claims 17 to 19, wherein the composition is dissolved in 120 ml of water and the viscosity of the composition is less than or equal to 26 cP as measured at rotation speed of 50 rpm using a Brookfield type viscometer spindle 2 Therapeutic pharmaceutical composition. The method of claim 1, wherein the bisphosphonate is sodium risedronate; the pH sensitive polymeric material is pectin; Bubble formers are sodium bicarbonate and citric acid; A buffer composition is a pharmaceutical composition for treating osteoporosis, which is an effervescent tablet or effervescent granules that are citric acid and sodium citrate. The method of claim 1, wherein the bisphosphonate is sodium ibandronate; the pH sensitive polymeric material is pectin; Bubble formers are sodium bicarbonate and citric acid; The buffer is a pharmaceutical composition for treating osteoporosis, which is effervescent tablets or effervescent granules are citric acid and sodium citrate. The method of claim 1, wherein the bisphosphonate is sodium alendronate; the pH sensitive polymeric material is pectin; Bubble formers are sodium bicarbonate and citric acid; The buffer is a pharmaceutical composition for treating osteoporosis, which is effervescent tablets or effervescent granules are citric acid and sodium citrate.

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