JP2018131403A - Hydrous pharmaceutical preparation of minodronic acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutically stable hydrous pharmaceutical preparation of minodronic acid (specifically, jelly agent) that even elderly persons can easily ingest.SOLUTION: As the present invention, there is provided a pharmaceutically stable hydrous pharmaceutical preparation (jelly agent is preferable) which contains minodronic acid or hydrate thereof and whose pH is within the range of 5 to 8 for example. In the case where the preparation of the present invention is a jelly agent, it is preferable that the breaking distortion factor of the agent is within the range of 55 to 80%. According to the present invention, a hydrous pharmaceutical preparation in which minodronic acid is dissolved into the preparation at high concentration can be provided. The hydrous pharmaceutical preparation according to the present invention is particularly effective to patients such as elderly persons having reduced swallowing function of a solid preparation.SELECTED DRAWING: None

Description

  The present invention belongs to the technical field of hydrous pharmaceutical preparations such as jelly agents. The present invention relates to a water-containing pharmaceutical preparation containing minodronic acid or a hydrate thereof (hereinafter also referred to simply as “minodronic acid”) as an active ingredient. Specifically, the present invention relates to a water-containing pharmaceutical preparation containing minodronic acid effective for the treatment of osteoporosis, which is pharmaceutically stable and suitable for the elderly.

In recent years, the number of elderly people has been increasing year by year, and the number of patients with osteoporosis is also increasing. Osteoporosis is a skeletal disease characterized by a decrease in bone strength and an increased risk of fracture.
Bisphosphonate drugs such as minodronate and alendronate are used for the treatment of osteoporosis. These bisphosphonate drugs are drugs that strongly suppress bone resorption by acting directly on osteoclasts, and have excellent therapeutic effects such as reducing bone fracture risk by increasing bone mass. doing.

  On the other hand, if the bisphosphonate drug remains attached or retained on the oropharynx during taking, it may cause side effects such as esophageal ulcer and esophagitis. For this reason, it is necessary to take the drug together with a large amount of water so that the drug does not adhere to or remain in the oropharynx. In addition, after taking, it is necessary to wake up the upper body for at least 30 minutes to prevent backflow from the stomach to the esophagus. Furthermore, since the absorption rate of the drug in the body is extremely low and is further lowered by eating and drinking, it is essential to fast for 30 minutes or more after taking, and the burden on the patient is very large.

  Patent Document 1 discloses an oral jelly-form preparation containing alendronic acid which is one of bisphosphonate drugs, a gelling agent, a polyhydric alcohol, and water. This oral jelly-form preparation is easy to swallow by making the dosage form a jelly form, and is difficult to adhere to or remain in the oropharynx. However, alendronic acid has high hydrophilicity, but its medicinal properties are relatively low, so it is necessary to dissolve a large amount of drug in the preparation, and it is difficult to contain more than one dose of drug per week. . For this reason, the frequency | count of taking cannot be reduced and it is difficult to fully reduce a patient's burden.

  Patent Documents 2 and 3 disclose high-dose tablets for oral administration containing a large amount of minodronic acid, a pharmaceutically acceptable salt, or a hydrate thereof, which is one of bisphosphonate drugs. Since this high-content tablet for oral administration contains a large amount of minodronic acid with high medicinal properties, the number of doses should be reduced from once a day to once a week or once every four weeks. It is possible to reduce the burden on the patient. However, such a tablet is not necessarily a dosage form that is easy to be taken by elderly people with many osteoporosis patients, and it poses a problem that it adheres to or remains in the oropharynx.

Minodronic acid is a third generation bisphosphonate drug, and has a medicinal effect 10 to 100 times higher than that of alendronate, which is a second generation bisphosphonate drug. However, since minodronic acid is extremely difficult to dissolve in water (solubility notation in the Japanese Pharmacopoeia, about 7.3 × 10 ⁻¹ mg / mL), it is difficult to obtain a water-containing pharmaceutical preparation.

JP 2012-046506 A International Publication No. 2005/072747 Japanese Patent No. 5874545

With regard to minodronic acid, conventionally, studies have been mainly conducted on solid preparations that are relatively easy to stabilize. However, a solid preparation can generally have a high content, but it is not always a dosage form that is easy for the elderly to take.
There have been few studies on high-dose minodronic acid hydrous pharmaceutical preparations that are easy to take for the elderly and have been reduced in the number of doses, and no such preparations have been found so far.

The main object of the present invention is to provide a pharmaceutically stable and novel water-containing pharmaceutical preparation suitable for taking by the elderly, containing minodronic acid effective for osteoporosis and the like.
Here, the “hydrated pharmaceutical preparation” refers to a pharmaceutical preparation in which an active ingredient is dissolved, dispersed or suspended in water, or a pharmaceutical preparation comprising a step of dissolving, dispersing or suspending an active ingredient in water in the production thereof. Basically, oily raw materials such as oil, fats and oils, and fats are not included, but may be included within a range not impairing the effects of the present invention. Specific dosage forms include, for example, jellies, syrups, solutions, emulsions, suspensions, injections, and dry syrups containing water during the manufacturing process.

  As a result of intensive studies, the present inventors have found that the above problem can be solved by at least adjusting the pH in the preparation to a certain range, and have completed the present invention.

Examples of the present invention include the following.
[1] A pharmaceutically stable water-containing pharmaceutical preparation comprising minodronic acid or a hydrate thereof and having a pH in the range of 5-8.
[2] The water-containing pharmaceutical preparation according to the above [1], wherein the concentration as minodronic acid is 0.5 to 8% by weight based on water.
[3] The hydrous pharmaceutical preparation according to the above [1] or [2], wherein minodronic acid or a hydrate thereof is dissolved in the preparation.
[4] The water-containing pharmaceutical preparation according to any one of the above [1] to [3], wherein minodronic acid is not precipitated in the preparation and is dissolved even in a refrigerated environment at 4 ° C.
[5] The water-containing pharmaceutical preparation according to any one of [1] to [4], further comprising citric acid or a hydrate thereof and sodium hydroxide as a pH adjuster.
[6] The water-containing pharmaceutical preparation according to any one of the above [1] to [5], wherein the water-containing pharmaceutical preparation is for oral use.

[7] The water-containing pharmaceutical preparation according to the above [6], further comprising a gelling agent.
[8] The hydrous pharmaceutical preparation according to the above [7], wherein the gelling agent comprises locust bean gum and xanthan gum.
[9] The water-containing pharmaceutical preparation according to any one of the above [6] to [8], wherein the water-containing pharmaceutical preparation is a jelly agent.
[10] The hydrous pharmaceutical preparation according to the above [9], wherein the breaking strain ratio is in the range of 55 to 80%.

[11] A method for producing a water-containing pharmaceutical preparation containing minodronic acid or a hydrate thereof, comprising the following steps (1) to (3): Production method.
(1) a step of dispersing minodronic acid or a hydrate thereof in an acidic aqueous solution;
(2) A step of adding an alkali after the dispersion to adjust the pH within a range of 5 to 8, and (3) a step of dissolving minodronic acid or a hydrate thereof within the range of the pH.
[12] The method for producing a water-containing pharmaceutical preparation according to the above [11], wherein the acidic aqueous solution contains citric acid or a hydrate thereof, and the alkali is sodium hydroxide.

According to the present invention, it is possible to provide a hydrous pharmaceutical preparation (for example, a jelly agent) that can maintain minodronic acid stably as a hydrous pharmaceutical preparation for a long period of time and can be easily taken even by an elderly person. In addition, since it can be a high content minodronic acid preparation, it is possible to reduce the number of doses and to improve the patient's quality of life (QOL). Can be provided.

It is a photograph showing the state of a time-dependent change of the water-containing pharmaceutical formulation (jelly agent) which concerns on this invention.

1 About the water-containing pharmaceutical preparation according to the present invention The water-containing pharmaceutical preparation according to the present invention (hereinafter referred to as “the present invention preparation”) contains minodronic acid or a hydrate thereof as an active ingredient and has a pH in the range of 5-8. And is pharmaceutically stable.

1.1 About Minodronic Acid Minodronic acid is a general name for [1-hydroxy-2- (imidazo [1,2-a] pyridin-3-yl) ethylidene] bisphosphonic acid, which is a type of bisphosphonate drug. Is a compound having the structure The preparation of the present invention contains this minodronic acid or a hydrate thereof. Examples of minodronic acid hydrates include monohydrate and dihydrate.
Minodronic acid hydrate is an active ingredient of an osteoporosis therapeutic agent such as Bonoteo (registered trademark) and Recarboxy (registered trademark) tablets.

1.2 State and content of minodronic acid The content of minodronic acid in the preparation of the present invention varies depending on the dosage form of the preparation of the present invention, but is suitably within the range of 0.1 to 10% by weight with respect to water. In the range of 0.3 to 9% by weight, preferably in the range of 0.5 to 8% by weight. If the amount is less than 0.1% by weight, the dosage of the preparation of the present invention may increase. If the amount is more than 10% by weight, there may be a problem in the solubility, dispersibility or suspendability of minodronic acid.
As content in the case of a jelly agent, the inside of the range of about 0.3-9 weight% is suitable, for example, and the inside of the range of about 0.5-8 weight% is preferable.
Since the present invention includes a high content of minodronic acid preparation, it can be a high-dose preparation of, for example, once every 4 weeks (in the case of 50 mg / 1 g preparation).

  Minodronic acid is in a dissolved or dispersed or suspended state in the preparation of the present invention or when water is included in the production process. Among these, it is particularly preferable that minodronic acid is dissolved in the preparation of the present invention. When dissolved, when the patient takes the preparation of the present invention, it is easy to confirm that there is no foreign body sensation and that there are no foreign objects in the preparation. Can give a good impression over the throat. The main medium of the preparation of the present invention is water, and examples of such water include normal water, purified water, and water for injection, and are not particularly limited as long as they are pharmaceutically acceptable.

1.3 Liquidity The preparation of the present invention is adjusted within the range of pH 5-8. As a result, the solubility and stability of minodronic acid in an aqueous solvent can be improved, and crystal precipitation of minodronic acid and generation of decomposition products (related substances), and coloration resulting therefrom can be suppressed. Preferably it exists in the range of pH 5.5-7.5. If the pH in the preparation is lower than 5, the solubility of minodronic acid is low and crystal precipitation is observed, and if the pH is higher than 8, there is a risk of problems in the stability of minodronic acid.

  For adjusting the liquidity, a pH adjuster can be used and is not particularly limited as long as it is pharmaceutically acceptable. Specifically, examples of the pH adjuster include phosphoric acid or a salt thereof, citric acid or a salt thereof, carbonic acid or a salt thereof, maleic acid, glycine, hydrochloric acid, sodium hydroxide and the like. Of these, citric acid or a salt thereof is preferable. One or more of these can be used in combination as appropriate. Moreover, buffer solutions, such as a phosphate buffer, a citrate buffer, a citrate phosphate buffer, and a carbonate buffer, can also be used.

1.4 Pharmaceutically stable The preparation of the present invention is a pharmaceutically stable preparation. Pharmaceutically stable means having the level of stability required in the review required to sell as a pharmaceutical product. It also means that the product has a level of stability that allows the quality to be maintained during the distribution of the drug. Specifically, it means that the preparation has properties such as long-term stability. For example, in the case of a jelly agent, it was exposed to low temperatures (refrigerated conditions of 4 ° C., 10 ° C. and 15 ° C., or -20 ° C. freezing conditions) and high temperatures (40 ° C., 50 ° C. and 60 ° C.). This means that it has long-term stability.

  Pharmaceutical stability is usually confirmed by a stability test of the preparation. In the test, the preparation is stored for a specified period of time under various environmental conditions (temperature, humidity, light, etc.). For example, by observing changes in appearance over time such as crystal precipitation and quantifying degradation products, Sex can be confirmed. The predetermined period is suitably 2 weeks or more, preferably 3 months or more, and more preferably 12 months or more.

1.5 Forms of the preparation of the present invention, other additives, and packaging materials As specific forms (dosage forms) of the preparation of the present invention, for example, jelly, syrup, liquid, emulsion, suspension, injection, production A dry syrup containing water may be mentioned during the process. Among these, a jelly agent is preferable.

Among the above forms, a gelling agent is usually used in order to obtain a jelly-like form (jelly agent). Such a gelling agent is not particularly limited as long as it can be pharmaceutically acceptable and can gel a liquid (water) into a viscous semi-solid, for example, high molecular polysaccharides, gelatin, Mention may be made of sodium polyacrylate. Of these, polymeric polysaccharides are preferred.
Specific examples of the polymer polysaccharide include pectin, agar, carrageenan, gellan gum, xanthan gum, locust bean gum, gum arabic, guar gum, tara gum, alginic acid or a salt thereof, and glucomannan. One or more of these can be used in combination as appropriate. The polymer polysaccharide has an appropriate pH for forming a gel state, and is appropriately selected according to the liquidity (pH) of the preparation of the present invention. For example, in the preparation of the present invention having a pH of 5 to 8, in order to maintain the gel state stably under these conditions, the combination of locust bean gum and xanthan gum, the combination of locust bean gum and carrageenan, or in addition to them The combined use of locust bean gum and xanthan gum is more preferred.

  The content of the gelling agent (eg, high molecular polysaccharide) in the preparation of the present invention varies depending on the gelling agent used, the pH of the preparation of the present invention, etc., but is usually in the range of 0.01 to 10% by weight. In the range of 0.03 to 5% by weight, more preferably in the range of 0.05 to 3% by weight. If the amount is less than 0.01% by weight, gelation may be insufficient. If the amount is more than 10% by weight, the gel may become too hard and trouble may occur in swallowing.

  Moreover, in order to improve the solubility of minodronic acid in water, for example, a solubilizer can be added. Examples of the solubilizer include a surfactant and an alcohol solvent.

  Additives other than those described above can be added as long as the effects of the present invention are not impaired. Examples of such additives include sweeteners, flavoring agents, fragrances, thickeners, preservatives, and excipients. These can be added at a concentration of 80% by weight or less in the preparation of the present invention.

Although the shape of the packaging material (container) for enclosing the preparation of the present invention is not particularly limited, for example, an ampoule shape, a vial shape, a cup shape, an envelope shape, a stick shape, a blister pack, and the like are appropriately selected. In particular, in consideration of portability and convenience during administration or administration, a stick-like one is preferable, although it depends on the final form of the preparation of the present invention.

2 Gel properties When the preparation of the present invention is a jelly agent (hereinafter referred to as “the jelly agent of the present invention”), the gel properties (jelly strength, strain rate at break) are further set within a predetermined range, so that patients, particularly elderly It is possible to make the preparation easier for a person to drink.

2.1 Jelly Strength The jelly strength (breaking stress) of the jelly agent of the present invention is suitably 1.0 × 10 ^{3 to} 1.5 × 10 ⁵ Pa, and 1.0 × 10 ^{4 to} 1.0. It is preferable that it is x10 < ⁵ > Pa. By setting the jelly strength within the above range, the shape as a jelly agent can be maintained, and in addition, the jelly agent can be easily swallowed and swallowed.

  The jelly strength can be measured by, for example, a breaking stress measuring device. For example, RHEONER RE2-3305C manufactured by Yamaden Co., Ltd. can be cited as an example of a breaking stress measuring device suitable for this purpose. For the measurement results, when plotting the stress-strain curve with the sample stress on the vertical axis and the sample compressive strain rate on the horizontal axis, the stress at the top of the convex shape (which is considered to be the rupture stress) is usually jelly. It becomes strength.

2.2 Breaking strain rate The breaking strain rate of the jelly agent of the present invention is preferably in the range of 45 to 95%, more preferably in the range of 55 to 80%. By making the breaking strain within the above range, it is possible to achieve both the dispersion of the formulation in the mouth and the ingestion, thereby suppressing the disintegration of the formulation in the mouth and the outflow of the drug, Oral pharyngeal irritation caused by acid and the stimulating action on the upper gastrointestinal mucosa can be suppressed, and the preparation can be made easier to be taken by the user, particularly the elderly with reduced swallowing function.

The strain rate at break is determined by compressing and deforming the jelly with a jig or the like. When the jelly that cannot withstand compression is in a state of breaking (breaking), the deformation rate of the jelly (with respect to the thickness of the original jelly, It represents the thickness when broken (broken) in percentage). Therefore, if the breaking strain rate is low, it is difficult to be deformed and easily collapsed (easy to break), and if the breaking strain rate is high, it is easily deformed and has properties that are difficult to collapse (not easily broken). means.

3. Manufacturing method of this invention formulation This invention formulation can be manufactured in accordance with the conventional method in each dosage form. In particular, when obtaining the preparation of the present invention in which minodronic acid is stably dissolved in water, a production method including the following steps (1) to (3) (hereinafter referred to as “the present invention production method”). It is preferable to manufacture.
(1) Step of dispersing minodronic acid or a hydrate thereof in an acidic aqueous solution (2) Step of adding an alkali after the dispersion and adjusting the pH within the range of 5 to 8 (3) Within the range of the pH Dissolving minodronic acid or its hydrate

  Step (1) is a step of dispersing minodronic acid in an acidic aqueous solution. In this step, the drug is dispersed in an acidic aqueous solution, preferably an aqueous solution containing citric acid or a hydrate thereof, by means such as stirring. The acidic aqueous solution contains water itself or a pH adjuster, a gelling agent, an additive and the like.

  The step (2) is a step of adding an alkali after the dispersion and adjusting the pH within the range of 5 to 8, preferably within the range of 5.5 to 7.5. In this step, the pH of the drug dispersion is adjusted with an alkali, preferably sodium hydroxide.

  The step (3) is a step of dissolving minodronic acid within the above pH range. In this step, minodronic acid is dissolved while stirring the drug dispersion.

According to the production method of the present invention including the steps described above, minodronic acid having a property that is extremely hardly soluble in water can be efficiently dissolved in an aqueous solvent at room temperature in a short time. The preparation of the present invention produced by the production method of the present invention exhibits pharmaceutically stable properties. The drug once dissolved can maintain a stable dissolved state for a long period of time.

4. Use of the preparation of the present invention The preparation of the present invention can be used in a pharmaceutically appropriate amount for the indication disease observed for minodronic acid. Examples of such indication diseases include osteoporosis, osteoarthritis, tumor bone metastasis, multiple osteomyeloma, osteogenesis imperfecta and the like. In particular, it is preferably used for the treatment of osteoporosis that is common in elderly people. The age of the indication patient is not particularly limited, but the preparation of the present invention is particularly excellent for taking the elderly with a swallowing function of the solid preparation.

  EXAMPLES Hereinafter, although an Example and a test example are hung up and this invention is demonstrated in more detail, this invention is not limited to these Examples. The “minodronic acid” described below is “minodronic acid monohydrate”.

Each test was performed as follows.
<Mindronic acid content measurement>
The content of minodronic acid was measured by high performance liquid chromatography (HPLC). HPLC measurement conditions are as follows.

Detector: UV absorptiometer (wavelength: 280 nm)
Column: A stainless tube having an inner diameter of 4.6 mm and a length of 25 cm filled with 5 μm of octadecylsilylated silica gel for liquid chromatography.
Column temperature: 40 ° C
Mobile phase A: 4.46 g of sodium diphosphate decahydrate was dissolved in 950 mL of water, adjusted to pH 2.2 by adding phosphoric acid, and accurately adjusted to 1000 mL.
Mobile phase B: A mixture of acetonitrile / mobile phase A for liquid chromatography (7: 3)

The mobile phase was fed by controlling the concentration gradient by changing the mixing ratio of mobile phase A and mobile phase B as shown in Table 1 below. The flow rate was adjusted so that the retention time of minodronic acid was about 6 minutes.

<Measurement of content of related substances>
The content of related substances was measured by HPLC, and the detector, column, column temperature, mobile phase and flow rate were in accordance with the content measurement of minodronic acid.
The mobile phase was fed by controlling the concentration gradient by changing the mixing ratio of mobile phase A and mobile phase B as shown in Table 2 below. The area measurement range was about 4 times the retention time of minodronic acid after the solvent peak (however, the peak derived from the formulation component was not measured).

<Measurement of water separation rate>
The jelly agent was taken out from the stick-like bag-like container, and the mass was accurately measured (W1). Next, the net was fixed to a container (W2) whose mass was accurately measured in advance. The contents of this product were taken out on a net so as not to collapse, and allowed to stand for 5 minutes. Thereafter, the mass of only the container was again accurately weighed (W3). After the measurement, the packaging material of this product was cut open, washed thoroughly, and then sufficiently dried to accurately measure the mass of the packaging material (W4).
The water separation rate was calculated by the following formula.

<Measurement of jelly strength>
The jelly agent was taken out from the stick-shaped bag-shaped container so that the contents did not collapse, and the rupture stress (jelly strength) was determined according to the test conditions using a rupture stress measurement device (RHEONER RE2-3305C manufactured by Yamaden Co., Ltd.).
After measuring the thickness of the sample in advance using the measurement table and measuring the thickness of the sample, the sample was measured at a speed of 10 mm / sec up to 95% of the thickness using a cylindrical measuring jig with a diameter of 5 mm. After compressing, the stress and compressive strain rate were measured by the above apparatus. When the stress-strain curve is plotted with the stress of the sample on the vertical axis and the compressive strain rate of the sample on the horizontal axis, the stress at the top of the convex shape is taken as the rupture stress (jelly strength).

<Measurement of fracture strain>
When measuring the jelly strength described above, the jelly is compressed and deformed with a measuring jig, and the jelly deformation rate when the jelly that can no longer withstand the compression breaks (breaks) is changed to the original jelly thickness. On the other hand, the thickness at the time when the jelly broke (ruptured) was measured as a percentage, and the fracture strain was determined.

[Test Example 1] Examination of pH The pH at which minodronic acid oral jelly was judged to be stable in appearance was examined. Samples of a jelly agent (pH 4.3, 4.9, 6.2, 7.3, 8.5) having a target pH by a conventional method were prepared according to the formulation shown in Table 3 below. Each target preparation was adjusted by appropriately changing the amount of sodium hydroxide added.
The test was performed by filling 1 g each of a bag-shaped container molded in a stick shape with a transparent plastic film, and after sealing, storing the jelly agent in an aluminum pillow under conditions of 60 ° C. and 75% relative humidity. It was. As a result of the test, the time-dependent change of the jelly agent was evaluated from the appearance. The result is shown in FIG.

As shown in FIG. 1, the pH 4.3 jelly agent was already cloudy at the time after preparation (room temperature product), and minodronic acid was precipitated. The other pH jelly agents were clear jelly. As a result of storage at 60 ° C., remarkable minodronic acid crystal aggregates were observed after 1 week at pH 4.3 and after 3 weeks at pH 4.9. All remained clear at the other pH.
At pH 6.2, 7.3, and 8.5, the jelly turned brown over time, and at pH 8.5, the appearance was unacceptable at 3 weeks.
Therefore, it was confirmed that in the minodronic acid jelly agent, pH 4.9 or higher and pH 8.5, that is, pH 5 to 8 had acceptable stability in appearance.

[Test Example 2] Evaluation of content and related substances The jelly agents (pH 4.9, 6.2, and 7.3) having the formulation shown in Table 3 were stored for 3 weeks in an environment of 60 ° C and 75% relative humidity. Then, the content of minodronic acid and the time course of related substances were measured, and the stability of the jelly agent at each pH was evaluated.

  Table 4 shows the results of measuring the change over time in the content of minodronic acid. The content maintained almost 100% at any pH, and the stability of the jelly agent was confirmed.

Table 5 shows the results of measurement of related substances. In the table, RRT (relative retention time) is shown as a relative value of peak retention times in chromatograms of various related substances based on the retention time of minodronic acid. Various related substance peaks have been detected, but refer to “Guidelines on Impurities of Drugs Among Drugs Containing New Active Ingredients” (H15.6.24 Pharmaceutical Proposal 06242001, H18.7.3 Medicinal Diet Examination Issue 0703004) The evaluation was based on a threshold value of 0.2% for determining the structure.
All of the related substances detected from each pH sample were within the range of 0.2%, and it was confirmed that there was no problem. However, the RRT 3.90 of the pH 4.9 sample was barely within the range of 0.2%, but it was a very high production amount of related substances. This was suggested in this study.

[Test Example 3] Stability study under low temperature environment According to the formulation shown in Table 6, using the jelly agent of the present invention prepared by a conventional method, under low temperature (refrigeration conditions of 4 ° C, 10 ° C and 15 ° C, or The stability when exposed to -20 ° C freezing conditions) was tested. As the jelly agent of the present invention, 1 g of a container molded in a stick shape with a transparent plastic film and filled in an aluminum pillow was used.
Test items include whether the gel properties specific to the jelly agent (jelly strength) are maintained, whether water separation does not occur (water separation rate), and whether there are precipitates, browning, etc. (appearance), A storage test was conducted in a low temperature environment.

  The test is a cycle test, that is, stored for 5 days under refrigeration (4 ° C., 10 ° C., and 15 ° C.) or frozen (−20 ° C.), and then stored at 25 ° C. for 2 days. Cycled. The appearance was confirmed every cycle, and after 4 cycles, the jelly strength and water separation rate were measured and evaluated.

The test results are shown in Table 7. In the column of the appearance, the case where there was no precipitate or browning change and no change in the appearance was observed is marked with ◯.
The state of the jelly before storage in a low-temperature environment was clear in appearance, no precipitate was observed, the jelly strength was 62,438 Pa, and the water separation rate was 0%. When stored at −20 ° C. for 5 days, the jelly was frozen and clouded, but when stored at 25 ° C. for 2 days, it thawed and the appearance was clear and no precipitate was observed. . Moreover, almost no change was observed in the jelly strength and the water separation rate. For other temperature zones (4 ° C, 10 ° C and 15 ° C), the appearance remains clear when stored for 5 days in each temperature zone, and the physical properties after returning to 25 ° C are strong. There were no problems such as a decrease or an increase in water separation rate, and the state before storage was maintained.
By this test, it was confirmed that the jelly agent of the present invention is stable under a low temperature environment.

[Test Example 4] Examination of gel physical properties Using the jelly preparation of the present invention prepared by a conventional method with the formulations shown in the upper column of Table 8 (gel strength, (Breaking strain rate) was examined. The test was conducted by measuring gel physical properties and sensory evaluation.

The result of the test is shown in the lower column of Table 8. As a result of sensory evaluation, the jelly agent of the present invention of Formulation A was very soft and very low in elasticity and barely maintained its shape. On the other hand, the jelly preparation of the present invention of Formula B had moderate hardness and strong elasticity.
From the above sensory evaluation and gel physical property measurement results, the elasticity suitable for the jelly agent of the present invention is considered to be between the two jelly agents tested, and the value of the breaking strain is about 55 to 80%. It was suggested that it was appropriate.

  Since the preparation of the present invention is excellent in stability and easy to take, it is particularly useful for patients such as elderly people whose swallowing function of a solid preparation is generally reduced.

Claims (12)

A pharmaceutically stable water-containing pharmaceutical preparation comprising minodronic acid or a hydrate thereof and having a pH in the range of 5 to 8. The water-containing pharmaceutical preparation according to claim 1, wherein the concentration of minodronic acid is 0.5 to 8% by weight based on water. The hydrous pharmaceutical preparation according to claim 1 or 2, wherein minodronic acid or a hydrate thereof is dissolved in the preparation. The hydrous pharmaceutical preparation according to any one of claims 1 to 3, wherein minodronic acid does not precipitate in the preparation and is dissolved even in a refrigerated environment at 4 ° C. Furthermore, the water-containing pharmaceutical formulation as described in any one of Claims 1-4 which contains a citric acid or its hydrate, and sodium hydroxide as a pH adjuster. The hydrous pharmaceutical formulation according to any one of claims 1 to 5, wherein the hydrous pharmaceutical formulation is for oral use. Furthermore, the water-containing pharmaceutical formulation of Claim 6 containing a gelatinizer. The water-containing pharmaceutical preparation according to claim 7, wherein the gelling agent comprises locust bean gum and xanthan gum. The water-containing pharmaceutical preparation according to any one of claims 6 to 8, wherein the water-containing pharmaceutical preparation is a jelly agent. The hydrous pharmaceutical preparation according to claim 9, wherein the breaking strain ratio is in the range of 55 to 80%. A method for producing a pharmaceutically stable hydrous pharmaceutical preparation comprising minodronic acid or a hydrate thereof, comprising the following steps (1) to (3):
(1) a step of dispersing minodronic acid or a hydrate thereof in an acidic aqueous solution;
(2) A step of adding an alkali after the dispersion to adjust the pH within a range of 5 to 8, and (3) a step of dissolving minodronic acid or a hydrate thereof within the range of the pH. The method for producing a water-containing pharmaceutical preparation according to claim 11, wherein the acidic aqueous solution contains citric acid or a hydrate thereof, and the alkali is sodium hydroxide.