KR102011714B1 - Oral emulsion formulation comprising Risedronic acid or its salts and vitamin D and the method for preparation thereof - Google Patents

Abstract

The present invention relates to an oral emulsion composition comprising vitamin D and risedronate, and discloses a stable single phase emulsion composition, which is convenient to manufacture compared to a tablet, and which does not have a decrease in the content of the main component or the occurrence of precipitates, and a method of preparing the same.

Description

Oral emulsion formulation comprising Risedronic acid or its salts and vitamin D and the method for preparation according to riseronic acid or its salt and vitamin D

The present invention relates to an emulsion composition containing risedronic acid or a salt thereof and vitamin D and a method for producing the same.

Osteoporosis refers to a condition in which bone strength is weakened and a fracture is likely to occur, and it is known as a disease caused by various factors including factors such as early menopause and steroids. Osteoporosis is a chronic disease that requires constant treatment during onset or disease.

Currently, drugs used to treat osteoporosis include calcium, vitamin D, bisphosphonate, and selective Estrogen Receptor Modulator (SERM). Of these, bisphosphonate preparations are the most widely used drugs, accounting for about 50% or more of the osteoporosis therapeutic market.

Bisphosphonate-based drugs (eg, alendronate, risedronate, ibandronate, etc.) generally have very low bioavailability so that up to about 1% is absorbed into the body even when taken orally according to the correct dosage method. About 50% of the absorbed bisphosphonates will selectively bind to bone. Bisphosphonates bound to the bones act on the activated osteoclasts and thus prevent calcium from escaping from the bones by preventing the bone resorption by the osteoclasts.

The osteoclast action of bisphosphonate-based drugs inhibits calcium outflow by inhibiting bone resorption, leading to lowered calcium in the blood, resulting in higher levels of parathyroid hormone in the blood. These reflexes cause side effects such as vitamin D deficiency, parathyroid function loss, renal function loss, and hypocalcemia.

For effective osteoporosis treatment, the intestinal absorption of calcium must be increased to address the problem of lowering calcium in the blood resulting from bisphosphonate therapy. Therefore, vitamin D levels in the blood are important. In the treatment of osteoporosis, the combination of vitamin D or its derivatives is recommended for the administration of bisphosphonate-based drugs, and vitamin D is generally used at 400 IU to 800 IU per day.

When the vitamin D compound is administered in combination with bisphosphonate drugs, the absorption of bone is suppressed by the bisphosphonate drugs, and at the same time, the absorption of dietary calcium in the small intestine is promoted by vitamin D, so that the blood calcium concentration is maintained within the normal range and fracture occurrence is prevented. Can be prevented.

Bisphosphonate containing formulations are most often in the form of solid formulations (eg, tablets) administered orally. If the tablet stays in the esophagus or stomach for a long time due to esophagus or delayed disintegration in the stomach after taking bisphosphonate tablets, there is a risk that the bisphosphonate-based drugs cause inflammation, bleeding or ulceration of the esophagus or gastrointestinal mucosa. have.

To reduce side effects such as irritation of the esophagus, gastrointestinal bleeding or ulceration due to mucosal irritation of bisphosphonate-based drugs, the bisphosphonate solids should be taken with 230 mL of water and remain standing for 30 minutes after taking them. There is discomfort in taking.

Most of the osteoporosis prevalence and onset patients who take the bisphosphonate preparations have a difficulty in taking solid preparations due to difficulty swallowing due to the elderly, and have low drug compliance due to the difficult drug administration method as described above. Literature data on actual drug use suggests that 56% of patients did not forget or obey one or more of the methods due to the tricky way of taking bisphosphonate preparations, and 29% of patients stopped taking it on average eight months. Was confirmed. (J Manag Care Pharm (1998), 4: 488-92).

Bisphosphonate-based drugs are water soluble, high in water solubility and stable in aqueous solution, while vitamin D is a fat-soluble drug, low in water solubility and soluble only in oily solvents. Vitamin D is a highly reactive substance and can be oxidized by contact with light, temperature or oxygen. In particular, the simple dissolution or mixing in solvents or other excipients accelerates the degradation resulting in reduced stability during manufacture and storage. [Reference: Jolanta Sawicka, Pharmazie 46, 1991]

A technique for preparing two active ingredients of bisphosphonate-based drugs and vitamin D having different physical properties in a stable single-phase formulation and improving and formulating a problem of lowering stability of vitamin D is still a problem to be solved.

J Manag Care Pharm (1998), 4: 488-92 Jolanta Sawicka, Pharmazie 46, 1991

Easily take oral bisphosphonate-based drugs and vitamin D in one dosage form, improving stability so that active ingredients do not precipitate or decrease, or lead to softening, and the homogeneous distribution of active ingredients. Development of one emulsion composition is required.

Accordingly, the present invention is an oral emulsion composition containing risedronic acid or a salt thereof and vitamin D as an active ingredient, inhibits the precipitation of active ingredients and the generation of analogues during manufacture and storage, and does not phase-separate the oil phase and the water phase, It is an object to provide a stable emulsion composition.

In order to solve the above problems, the present invention provides an oral emulsion composition comprising risedronic acid or a salt thereof and vitamin D and a method for producing the same.

Specifically, the present invention relates to an oral emulsion composition comprising the active ingredient risedronic acid or a salt thereof and vitamin D, respectively, in an aqueous phase and an oil phase.

Emulsion composition according to the present invention, the production and storage of the active ingredient inhibits the precipitation and generation of flexible substances, the content of the active ingredient is not lowered, the oil phase and the water phase is not phase-separated, maintain a stable dispersion form, and The stability of the components is secured. When the emulsion composition has an unstable dispersion form, the active ingredient particles may precipitate, leading to a decrease in the main ingredient content and the dissolution rate, a flexible substance may occur, and may cause problems such as a decrease in body absorption and bioavailability.

In the emulsion composition of the present invention, risedronic acid or a salt thereof is dissolved in water such as purified water or sterile water to form an aqueous phase, and vitamin D is dissolved in oil and a surfactant to form an oil phase. The oil and surfactant form an oil phase by solubilizing vitamin D, a fat-soluble substance, and maintain a stable colloidal state inside an aqueous phase containing risedronic acid or a salt thereof.

The emulsion composition of the present invention may further include an antioxidant, a buffer, a preservative, a solvent (eg, a low alcohol), and the like.

In the emulsion composition of the present invention, as the pharmaceutically acceptable oil, one or more selected from medium chain triglycerides, corn oil, polyethylene glycol dicaprylocaprate and the like may be used. Preferably, the medium chain triglycerides (for example, 6 carbon atoms) are used. To medium, preferably 8 to 10 carbon chain triglycerides) can be used.

The surfactant in the emulsion composition of the present invention is a pharmaceutically acceptable one selected from polyoxyl 35 hardened castor oil, polyethylene glycol 40 hardened castor oil, polyethylene glycol 400, caprylocaproyl macrogol-8-glyceride, and the like. The above can be used, Preferably polyoxyl 35 hardened castor oil can be used.

In the emulsion composition of the present invention, the antioxidant prevents the solvent containing the active ingredient from being exposed to the external environment, and also delays or prevents the rancidity of the prepared emulsion. In the emulsion composition of the present invention, as the antioxidant, butylhydroxyanisole, butylhydroxytoluene, tocopherol acetate, ascorbic acid, citric anhydride, etc. may be used, and preferably butylhydroxy toluene may be used.

The composition of the present invention may further include a pharmaceutically acceptable additive for oral administration within the scope of not impairing the effects of the present invention.

The present invention also relates to a method for preparing an oral emulsion composition comprising risedronic acid or a salt thereof and vitamin D.

The emulsion composition for oral use according to the present invention is prepared by separating the aqueous phase containing risedronic acid or a salt thereof and the oil phase containing vitamin D, and then mixing them. If the oil phase and the water phase are not prepared separately, the phases may separate or precipitate may occur.

In the production process according to the invention, the aqueous phase can be prepared by dissolving risedronic acid or its salt in water at room temperature or warmed up, and the oil phase can be prepared by dissolving vitamin D in a mixture of oil and surfactant. The buffer and / or preservative may be further dissolved in water in the preparation of the aqueous phase. In addition, the antioxidant may be further dissolved in a mixture of oil and surfactant in the oil phase preparation.

On the other hand, in the present invention, after preparing the aqueous phase containing risedronic acid or a salt thereof, it is preferable to cool it to about 30 ℃ or less, and then mix it with the oil phase. Since vitamin D is sensitive to temperature, light and the like, it is preferable to prepare an oil phase containing vitamin D at a temperature of 30 ° C. or lower, and mix it with an aqueous phase. If the oil phase is prepared or mixed with the water phase at a temperature exceeding 30 ° C., the content of vitamin D may be lowered or the softening material may increase, causing stability problems.

Meanwhile, antioxidants, buffers, preservatives, and the like may be further mixed in the mixture of the aqueous and oil phases as necessary.

In the composition of the present invention, risedronic acid or a salt thereof may be contained in the range of 0.1% (w / v) to 1% (w / v) with respect to the total composition, and vitamin D is 0.0001% (w / v). To 0.01% (w / v).

The oral emulsion composition of the present invention thus prepared may be formulated by filling in a bottle or pouch according to a conventional pharmaceutical preparation process.

Emulsion composition according to the present invention, the production and storage of the active ingredient inhibits the precipitation and generation of flexible substances, the content of the active ingredient is not lowered, the oil phase and the water phase is not phase-separated, maintain a stable dispersion form, and The stability of the components is secured.

1 shows the properties immediately after the preparation of the compositions of Examples 1 to 6 and Comparative Examples 1 and 2 of the present invention.

Hereinafter, the present invention will be described in more detail based on the following examples. However, the following examples are only for illustrating the present invention, and the spirit or scope of the present invention is not limited to the following examples.

Experimental Example 1 Surfactants and Oil Screening

Experimental Example 1 is for selecting an oil and a surfactant suitable for preparing an oil phase containing vitamin D.

After mixing the oil and the surfactant of Table 1 in a weight ratio of 1: 1, the phase is first confirmed whether the phase separation occurs, and only the composition without the phase separation of the oil and the surfactant is equivalent to 5600 IU After weighing and dissolving the vitamin D, the properties of the precipitates were secondary.

oil Surfactants Constellation Primary Secondary Medium Chain Triglycerides Polyoxyl 35 Cured Castor Oil - - Medium Chain Triglycerides Polyethylene Glycol 40 Cured Castor Oil + Medium Chain Triglycerides Polyethylene glycol 400, + Medium Chain Triglycerides Caprylocaproyl macrogol-8-glycerides + Corn Oil Polyoxyl 35 Cured Castor Oil - - Corn Oil Polyethylene Glycol 40 Cured Castor Oil + Corn Oil Polyethylene glycol 400, + Corn Oil Caprylocaproyl macrogol-8-glycerides + Polyethylene Glycol Dicapryl Ocaprate Polyoxyl 35 Cured Castor Oil - - Polyethylene Glycol Dicapryl Ocaprate Polyethylene Glycol 40 Cured Castor Oil - ++ Polyethylene Glycol Dicapryl Ocaprate Polyethylene glycol 400, + Polyethylene Glycol Dicapryl Ocaprate Caprylocaproyl macrogol-8-glycerides +

(+: Phase separation occurs, ++: precipitate occurrence,-: no change)

Experimental results showed that polyethylene glycol dicaprylocaprate, medium chain triglycerides, corn oil and a mixture of polyoxyl 35 hardened castor oil were the most preferred solvents for oil phase preparation.

Experimental Example 2 Optimal Ratio Screening of Oils and Surfactants

Experimental Example 2 is an experiment for finding the optimum ratio of the oil and surfactant selected through Experimental Example 1 above.

First, after preparing an oil phase, it was dispersed in an aqueous phase (purified water) in which risedronate was dissolved, to prepare a composition, and after 24 hours after the preparation, the change in properties of the composition was confirmed.

Each oil (ie, medium chain triglyceride, corn oil, polyethylene glycol dicaprylocaprate) selected through Experimental Example 1 and polyoxyl 35 hardened castor oil, which are surfactants, were prepared in a predetermined weight ratio, and then this mixture (oil phase) The mixture was dispersed in 20 mL of purified water at a weight ratio of 0.3%, and the change in appearance after 24 hours was observed, and the results are shown in Table 2 below.

oil Oil: Surfactant (Characteristic) 9: 1 7: 3 5: 5 3: 7 1: 9 Medium Chain Triglycerides + + + - ++ Corn Oil + + + ++ ++ Polyethylene Glycol Dicapryl Ocaprate + + + + ++

(+: Phase separation, ++: precipitate occurrence,-: no change)

As a result of Table 2, when the mixture of corn oil and polyoxyl 35 hardened castor oil was dispersed in the aqueous phase irrespective of the ratio, phase separation occurred and precipitates occurred.

On the other hand, when the heavy chain triglycerides and polyoxyl 35 hardened castor oil were mixed when the weight ratio was 3: 7, it was confirmed that the oil phase was stably dispersed in the aqueous phase. Therefore, in the present invention, it is preferable that the weight ratio of the medium chain triglycerides and polyoxyl 35 hardened castor oil is 4: 6 to 2: 8.

[Examples 1 to 6] Preparation of the Compositions of the Invention

Examples 1 to 6 were prepared in the emulsion composition stable to the content shown in Table 3 by using the surfactant and the oil selected through Experimental Examples 1 and 2 as an oil phase.

Specifically, after dissolving sodium risedronate in purified water to confirm the properties, the aqueous phase is prepared by adding a buffer, a preservative, a sweetening agent, a flavoring agent, etc., and vitamin D is dissolved in a mixture of an oil (solvent) and a surfactant to confirm the properties. After adding an antioxidant to prepare an oil phase. Thereafter, the oil phase and the water phase were mixed to prepare an emulsion composition.

Unit:% (w / v) Raw material name Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Active ingredient Sodium riseronate 0.175 0.175 0.175 0.175 0.175 0.175 Buffer Citric Acid Hydrate 0.25 0.25 0.25 0.25 0.25 0.25 Buffer Sodium citrate 0.1 0.1 0.1 0.1 0.1 0.1 Sweetener Sucralose 0.03 0.03 0.03 0.03 0.03 0.03 Preservative Methyl paraoxybenzoate 0.008 0.008 0.008 0.008 0.008 0.008 Preservative Paraoxybenzoic acid propyl 0.002 0.002 0.002 0.002 0.002 0.002 Flavor Essence oil q.s q.s q.s q.s q.s q.s Active ingredient Vitamin D 0.0007 0.0007 0.0007 0.0007 0.0007 0.0007 solvent Medium Chain Triglycerides 0.09 0.09 0.09 0.09 0.09 0.09 Surfactants Polyoxyl 35 castor oil 0.21 0.21 0.21 0.21 0.21 0.21 Antioxidant Butylhydroxyanisol 0.01 0.005 Antioxidant Butylhydroxytoluene 0.01 0.005 Antioxidant Tocopherol Acetate 0.1 0.05

[ Comparative example  1 and 2] Comparative example  Composition preparation

The compositions of Comparative Examples 1 and 2 were prepared in the same manner as in Preparation Methods of Examples 1 to 6 with the components and contents shown in Table 4 below.

Unit:% (w / v) Raw material name Comparative Example 1 Comparative Example 2 Active ingredient Sodium riseronate 0.175 0.175 Buffer Citric Acid Hydrate 0.25 0.25 Buffer Sodium citrate 0.1 0.1 Sweetener Sucralose 0.03 0.03 Preservative Methyl paraoxybenzoate 0.008 0.008 Preservative Paraoxybenzoic acid propyl 0.002 0.002 Flavor Essence oil q.s q.s Active ingredient Vitamin D 0.0007 0.0007 solvent Medium Chain Triglycerides 0.09 0.09 Surfactants Polyoxyl 35 castor oil 0.21 0.21 Antioxidant Butylhydroxytoluene - 0.02

[ Experimental Example  3] Antioxidant Screening

Examples 1 to 6 and Comparative Example 1 confirmed the change of the composition and the content of vitamin D content under severe conditions (60 ℃ / RH80%), the results are shown in Table 5 below.

In this experimental example, in order to confirm the change in appearance, after centrifugation for 10 minutes at 3000rpm stored samples, it was confirmed whether the precipitate is present in the container.

Vitamin D Content (%) Constellation Initial 3 days 5 days Initial 3 days 5 days Example 1 - - - ++ Example 2 - - - ++ Example 3 103.17 100.96 101.56 - - - Example 4 104.91 96.54 96.07 - - - Example 5 - - - + Example 6 102.01 94.44 89.79 - - - Comparative Example 1 101.49 85.48 73.25 - - - Comparative Example 2 - - - ++ - -

(+: Phase change, ++: precipitate occurrence,-: no change)

Table 5 and Figure 1, it can be seen that the composition of Comparative Example 1, which does not contain an antioxidant, but did not change the properties of the vitamin D content is lowered, the stability is lowered.

The compositions of Examples 1 and 2 comprising butyl hydroxyl anisol as an antioxidant can be seen that precipitates occur in the emulsion immediately after preparation, resulting in poor stability.

Compositions of Examples 5 and 6, which contain tocopherol as an antioxidant, had a high tocopherol content (Example 5) and a change in properties, and a low tocopherol content (Example 6). It can be seen that this decreases.

On the other hand, the composition of Examples 3 and 4 using butylhydroxytoluene as an antioxidant was confirmed that the content of vitamin D is maintained stably, there is no change in appearance.

Compared with Example 4, it can be seen that the composition of Example 3, which has a relatively high content of butylhydroxytoluene, is more stable.

On the other hand, it can be seen that the composition of Comparative Example 2 prepared by further increasing the amount of butylhydroxytoluene, rather, precipitates are generated, resulting in poor property stability.

Thus, butylhydroxytoluene in the composition of the present invention is in the range of about 0.0005% (w / v) or more and about 0.02% (w / v), preferably about 0.005% (w / v) or more and about 0.015% (w / v). v) It is preferably contained in the following content.

Experimental Example 4 Stability test

In Experimental Example 4, the content of each active substance was changed after 3 months and 6 months under the long-term storage conditions (25 ℃ / RH 60%) and accelerated storage conditions (40 ℃ / RH 75%) of the composition of Example 3 will be. The results are shown in Tables 6 and 7 below.

Long-term storage Vitamin D Content (%) Risedronate content (%) Initial 3 months 6 months Initial 3 months 6 months Example 3 100.13 99.23 100.79 99.2 98.9 97.8

Accelerated Storage Vitamin D Content (%) Risedronate content (%) Initial 3 months 6 months Initial 3 months 6 months Example 3 100.13 100.01 97.79 99.2 98.6 98.9

As a result of Table 6 and Table 7, it was confirmed that the composition of Example 3 of the present invention maintains a stable single-phase emulsion composition without decreasing the content of the two active ingredients in each storage condition.

The bisphosphonate emulsion composition of the present invention, during the manufacture and storage of the active ingredient inhibits the precipitation and formation of a flexible material, the content of the active ingredient is not lowered, the oil phase and the water phase is not phase separated, and maintains a stable dispersion form, The stability of the components is secured.

Claims (10)

An aqueous phase comprising risedronic acid or a salt thereof; And
Including oil phases containing vitamin D, oils and surfactants,
The oil is at least one selected from the group consisting of medium chain triglycerides, corn oil, polyethylene glycol dicaprylocaprate,
The surfactant is an emulsion composition, characterized in that polyoxyl 35 hardened castor oil. The emulsion composition according to claim 1, wherein the oil phase is emulsified in the aqueous phase. delete delete The oral emulsion composition of claim 1, wherein the oil is a medium chain triglyceride. 6. The oral emulsion composition according to claim 5, wherein the weight ratio of the medium chain triglyceride to the polyoxyl35 hardened castor oil is 4: 6 to 2: 8. The emulsion composition of claim 1, further comprising an antioxidant. 8. The emulsion composition of claim 7, wherein the antioxidant is butylhydroxytoluene. The emulsion composition of claim 8, wherein the butylhydroxytoluene is included in an amount of 0.005% (w / v) to 0.015% (w / v) with respect to the emulsion composition. The method of claim 1, wherein risedronic acid or a salt thereof is contained in the range of 0.1% (w / v) to 1% (w / v) with respect to the total composition, vitamin D is 0.0001% (w / v) to Emulsion composition, characterized in that contained in the range of 0.01% (w / v).

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