KR100818701B1 - Ibuprofen oral solid preparation composition - Google Patents

Abstract

The present invention relates to a new oral solid formulation of ibuprofen that is poorly soluble in water, and more particularly to an ibuprofen oral solid formulation comprising ibuprofen, poloxamer, sodium lauryl sulfate and a hydrophilic polymer.

Since the composition of the present invention uses a smaller amount of excipient than the conventional ibuprofen solid preparation, it is convenient to take and improves patient compliance as well as a new ibuprofen oral which improves the bioavailability of ibuprofen by increasing the solubility of poorly soluble ibuprofen. Solid preparation composition.

Description

Ibuprofen oral solid preparation composition {Novel oral solid composite containing ibuprofen}

The present invention relates to an ibuprofen oral solid preparation composition using solid dispersion formation.

Ibuprofen is widely used as a nonsteroidal analgesic antipyretic agent, but has a problem of low bioavailability when administered orally because it is poorly soluble in water. Therefore, prodrugs (Bansal et al., Pharmazie, 49, 422-424, 1994; Murtha et al., J. Pharm. Sci., 83, 1222-1228, 1994) were used to increase the solubility of poorly soluble ibuprofen. However, prodrugs are still under investigation because they are new drugs and require toxicological tests, and clathrate compounds using betacyclodextrin (Ghorab and Adeyeye, Pharm. Dev. Technol., 6, 305-314, 1994 Attempted to solve the problem, but it did not increase the solubility of the poorly soluble drug ibuprofen and is not applied as a real product. Eutectic mixtures such as menthol (Miguel, Reg. Anesth., 19, 75-76, 1994; The solubility of ibuprofen, a poorly soluble drug by Jr. Wagner et al., J. Dermatol. Surg. Oncol. 20, 148-150, 1994), is increased but liquefied at room temperature. Microspheres (Bodmeier et al., J. Microencapsul., 9, 89-98, 1992; Kachrimanis et al., J. Pharm. Sci., 89, 250-259, 2000) and solid dispersion systems (Bodmeier and Wang, J. Pharm. Sci., 82, 191-194, 1993; Greenhalgh et al., J. Pharm. Sci. 88, 1182-1190, 1999) added excipients of waxes, colloidal polymers, methacrylic polymers and polyethylene glycols. Attempts have been made to increase the solubility of ibuprofen, but not only did not significantly increase the solubility of the poorly soluble drug, but the amount of excipient used is 2 to 10 times greater than the amount of ibuprofen drug, which has the disadvantage of increasing the capacity of the actual product. It was impossible to commercialize it.

Currently, oral commercially available ibuprofen suspending agents (e.g., bufenfen syrup ^TM ) are products which are suspended in an aqueous solution by adding surfactants and suspending agents to poorly water-soluble and hydrophobic ibuprofen, depending on the viscosity of the suspending agent during oral administration. Because of its high viscosity, it is inconvenient to take it and the taste of the surfactant is not good, so I feel refusal to take it. In addition, the bioavailability of ibuprofen is poor because it is a suspending agent (Bodmeier and Wang, J. Pharm. Sci., 82, 191-194, 1993; Greenhalgh et al., J. Pharm. Sci. 88, 1182). -1190, 1999). In addition, in order to solve the problem of the existing suspension, an attempt to commercialize the liquid by adding menthol, which forms a eutectic mixture with ibuprofen, to increase the solubility of ibuprofen (Miguel, Reg. Anesth., 19, 75- 76, 1994; Jr. Wagner et al., J. Dermatol. Surg. Oncol. 20, 148-150, 1994), but menthol alone was not successful because it showed no satisfactory increase in solubility of ibuprofen. Another invention related to oral ibuprofen solution is an example of eliminating the above-mentioned disadvantages and increasing the bioavailability of poorly soluble drugs, as well as the discomfort and rejection of taking conventional oral ibuprofen preparations (Korean Patent Application No. 2005- 0007652).

The present invention solves the drawbacks of existing ibuprofen formulations, while achieving improved bioavailability of ibuprofen by increasing the solubility of poorly soluble ibuprofen, and at the same time, it is convenient and easy to take by using a lower amount of excipients than conventional ibuprofen solid preparations. It is an object to provide a solid, non-liquid, ibuprofen oral solid preparation composition that can increase the compliance.

The present invention relates to an ibuprofen oral solid preparation composition comprising 4-7 wt% of poloxamer, 0.05-0.1 wt% of sodium lauryl sulfate, 20-30 wt% of a hydrophilic polymer and 50-75 wt% of ibuprofen as an active ingredient. .

Referring to the present invention in more detail as follows.

The ibuprofen oral solid preparation composition according to the present invention improves the bioavailability by increasing the solubility of poorly soluble ibuprofen, although the amount of ibuprofen as an active ingredient is 50% or more, even though a much smaller amount of excipient is used than the conventional ibuprofen solid preparation. In this way, convenience of taking and improvement of patient compliance were achieved. In addition, unlike the conventional solid dispersion preparation, when the solution is prepared by spray drying at 35-45 ℃ by applying a slight temperature rather than at room temperature, the solubility of ibuprofen can be further improved.

Hereinafter, the respective components of the ibuprofen oral solid preparation composition according to the present invention will be described in detail.

Poloxamer is known as a dissolution aid for poorly soluble drugs, but this poloxamer alone is ineffective as a dissolution aid for ibuprofen. Solubility of ibuprofen when a solid dispersion is prepared by spray drying with the following hydrophilic polymer Discovering the fact that it increases the present invention was completed. In the present invention, one or more mixtures selected from commercially available poloxamers, preferably selected from P 188 and P 407 and the like, may be used. It is preferable that the said poloxamer is contained 4-7 weight% in the ibuprofen oral solid preparation composition of this invention. If the amount of poloxamer is less than 4% by weight, no matter how much the solubility of ibuprofen is obtained even if the solid dispersion is prepared by spray drying with addition of the following hydrophilic polymer. In addition, when the amount of poloxamer is greater than 7% by weight, it shows the maximum solubility, but the amount of excipient is increased to provide convenience of administration.

It is preferable to contain 20-30 weight% of hydrophilic polymers in the ibuprofen oral solid preparation composition which concerns on this invention. Specific examples of the hydrophilic polymer include hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and methyl cellulose, and these may be selected or used in a mixture of two or more thereof. If the amount of the hydrophilic polymer is less than 20% by weight, the solubility of the produced ibuprofen solid dispersion is not only a problem, but the fluidity is not so good that the value of the product is low, and the amount of the hydrophilic polymer is greater than 30% by weight of the excipient. The amount of is increased so that there is no convenience of administration.

In the ibuprofen oral solid preparation composition according to the present invention, sodium lauryl sulfate is preferably contained 0.05 to 0.1% by weight. If the amount of sodium lauryl sulfate is less than 0.05% by weight, the ibuprofen oral solid preparation composition is attached to the spray dryer, so that the yield cannot be produced at about 30-40%, and when the amount of sodium lauryl sulfate is more than 0.1% by weight, High doses of sodium uryl sulfate can cause side effects, such as poor digestive absorption.

The content of the components in the composition according to the present invention is based on the total weight of the composition. In addition to the above components, the composition according to the present invention may include other pharmaceutically acceptable excipients such as lactose, corn starch and the like.

In the method for preparing the ibuprofen oral solid preparation composition according to the present invention, it is preferable to spray dry the solution while heating to 35-45 ° C. If the solution is spray dried at less than 35 ℃, there is no satisfactory increase in solubility. If the solution is sprayed at more than 45 ℃, the nozzle is clogged when spray drying the solution. As such, when the spray drying method is used, the ibuprofen oral solid preparation composition according to the present invention forms a particle-attached solid dispersion.

The composition thus prepared can form an effective particle solubility and bioavailability improvement even when only a small amount of excipients are formed by forming a solid dispersion with particles.

Another aspect of the present invention provides a method for preparing a polymer comprising: (1) dissolving poloxamer, sodium lauryl sulfate and a hydrophilic polymer in water, and

(2) suspending the ibuprofen drug in the solution of (1) and then spray drying with warming to 35-45 ° C.,

It relates to a method for preparing the ibuprofen oral solid preparation composition according to the present invention.

The method of formulating the ibuprofen oral solid preparation composition according to the present invention may be prepared in pharmaceutical form by methods well known to those skilled in the art. Examples thereof include tablets, calcels, and granules.

As described above, the present invention, the total excipient content except for the active ingredient is a solid agent is greatly reduced, and the convenience and patient compliance of the dose is greatly improved, and at the same time, the ibuprofen in vivo by increasing the solubility of poorly soluble ibuprofen Provided is an ibuprofen oral solid preparation composition with greatly improved utilization.

The amount of all excipients except the active ingredient ibuprofen in the composition of the present invention is 25 to 50% by weight, which is considerably smaller than in the conventional ibuprofen formulation as well as in the general formulation composition. Since the use of such a small amount of excipients is convenient to take it is expected to greatly improve patient compliance.

In addition, the solid preparation composition according to the present invention is easy to prepare a method to provide a very good formulation composition in terms of economics.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited by Examples.

Example  1 to 8

Next, the poloxamer, sodium lauryl sulfate and hydrophilic polymer were dissolved in water at room temperature with a composition as shown in Table 1, and the ibuprofen drug (used after passing 60 mesh sieve) was suspended in this solution, followed by a slight temperature (about 35 Spray drying with (-45 ° C.) to prepare an oral solid formulation for ibuprofen. The SEM photograph of the ibuprofen oral solid preparation composition of Example 8 is as shown in FIG. 1. The ibuprofen drug is in crystalline form, whereas the ibuprofen oral solid preparation composition is amorphous.

(Unit: g) division Example Comparative example One 2 3 4 5 6 7 8 One 2 3 4 5 Ibuprofen 50 75 65 68 72 68 62.9 75 75 75 75 75 75 Poloxamer P 407 5 2 4.95 - 4 7 7 7 4 9 7 7 7 P 188 - 2.9 - 7 3 - - - - - - - - Hydrophilic Polymer HPMC 20 - 30 - 20 - 30 30 30 30 30 15 45 MC - 20 - - - 20 - - - - - - - CMC-Na - - - 20 - - - - - - - - - Sodium Lauryl Sulfate 0.05 0.1 0.05 0.05 0.05 0.05 0.1 0.06 0.06 0.06 - 0.06 0.03 Excipient Corn starch 24.95 - - - 0.45 4.95 - - 2.5 - - 15 - Lactose - - - 4.95 0.5 - - - - - - - - Sum 100.00 100.00 100.00 100.00 100.00 100.00 100.00 112.06 111.56 114.06 112.00 112.06 127.03

* HPMC: Hydroxypropyl Methyl Cellulose

* MC: methyl cellulose

* CMC-Na: Sodium Carboxymethyl Cellulose

For the determination of ibuprofen HPLC  Condition

C18 column (25 cm × 0.46 cm I.D., particle size 5.0 μm)

Flow rate 1.2 ml / min

Injection volume 50 μl

UV wavelength 220 nm

Mobile phase acetonitrile / phosphate buffer (pH 3.5) (4: 6)

Experimental Example  1: Evaluation of Solubility of Ibuprofen in Aqueous Solution

Prepare Examples 1-8 and Comparative Examples 1-5 prepared above, add the excess (100 mg) to 10 ml of purified water, put it in a vial, seal it, stir at room temperature for 7 days, and then filter with Millipore filter. The solubility of ibuprofen was measured by high performance liquid chromatography (HPLC). As shown in Table 2, the maximum solubility is 50-65 mg / 100 ml when the ibuprofen oral solid preparation composition of the present invention contains 4-7 wt% of poloxamer, and the solubility is less than 4% wt% (Comparative Example 1). Lowered to 25 mg / 100 ml. In addition, the hydrophilic polymer exhibits a maximum solubility of 50-65 mg / 100 ml when contained in 20-30% by weight, regardless of the type such as hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and methylcellulose (comparative example). 4), the solubility is lowered to less than 30 mg / 100ml.

Experimental Example  2: ibuprofen oral Solid preparations  Yield of the composition

The results obtained by measuring the yields of Examples 1 to 8 and Comparative Examples 1 to 5 prepared above were as shown in Table 2. Yield of ibuprofen oral solid preparation composition showed more than 90% when sodium lauryl sulfate was added in 0.05 ~ 0.1% irrespective of the type and amount of poloxamer and the type and amount of hydrophilic polymer. (Comparative Examples 3 and 5) The ibuprofen oral solid preparation composition was attached to the spray dryer container, and the yield remained only at about 30%.

Experimental Example  3: ibuprofen oral Solid preparations  Flowability of the Composition

Examples 1 to 8 and Comparative Examples 1 to 8 prepared above were prepared, and the flowability of the composition was measured by the fixed-cone method in the angle of repose measurement. In other words, install a disc at the bottom of the powder tester (Hosokawa Micron, Japan) and place a funnel, a 24 mesh sieve, and a cylinder with top and bottom, which are in turn, 10 cm above the bottom of the disc. Device. The powder property measuring instrument was dropped about 10 g of the solid preparation composition while giving a constant vibration (180 sec / 60 cycle supply), and then the angle of the sample formed on the disk was measured with a protractor which is a powder measuring device structure. The results of measuring the angle of repose were shown in Table 2. The fluidity (rest angle) of the ibuprofen oral solid preparation composition was excellent at 35 ° or less when the hydrophilic polymer was added in an amount of 20% or more regardless of the type and amount of poloxamer and the type and amount of sodium lauryl sulfate, but the hydrophilic polymer was 20 If it was less than% (Comparative Example 4), the fluidity was greatly reduced to 50 ° or more, which contained problems during tableting and capsule filling.

Experimental Example  4: oral ibuprofen sprayed at room temperature and 35-45 ° C Solid preparations  Evaluation of Aqueous Solubility of Ibuprofen in Compositions

Example 8 (1) prepared by spray drying at 35-45 ° C. and Example 8 (2) prepared by spray drying at room temperature were respectively added to 10 ml of purified water and put into a vial. After sealing, the mixture was stirred at room temperature for 7 days, filtered through a Millipore filter, and the solubility of ibuprofen was measured by UV at 220 nm. The solubility of Example 8 (1) prepared by spray drying at 35-45 ° C. and Example 8 (2) prepared by spray drying at room temperature, unlike the present invention, was 60.1 ± 4.7 mg / 100 ml and 19.8 ± 3.5 mg / 100 ml. Therefore, the ibuprofen oral solid preparation composition prepared by spray drying at 35-45 ° C. as in the present invention increases the solubility by about three times that of the composition prepared at room temperature.

Experimental Example  5: stability test at room temperature

The composition of Example 8 prepared above was 25 ℃ and 45 ℃ The content of ibuprofen was measured while storing at 12 months. About 30 mg of the composition of Example 8 (20 mg equivalent of ibuprofen) was added to 20 ml of ethanol, stirred for 5 minutes, filtered through a Millipore filter, and quantified by high performance liquid chromatography (HPLC).

As a result, as shown in the following Table 3, the composition and the ibuprofen content of the composition of Example 8 were not significantly different for 12 months, and the ibuprofen content was maintained at 95% or more at 25 ° C and 45 ° C. It can be seen that it is stable for at least one year at ℃.

Experimental Example  6: internal dynamics test

Example 8 (10 mg / kg equivalent amount of ibuprofen) and ibuprofen drug powder (10 mg / kg) were orally administered to SD rats, and blood was collected from the femoral artery, and then contained an internal standard solution (flufenamic acid). Cut back by adding acetonitrile. After centrifugation, the supernatant was volatilized with nitrogen gas, a mobile phase was added, and quantified by high performance liquid chromatography (HPLC).

As a result, as shown in FIG. 2, the composition of Example 8 was found to have a very high blood concentration significantly from the beginning to the middle stage when the drug alone and the blood concentration were compared. In addition, as shown in Table 4, Cmax was significantly increased by about 11 times and AUC by about 9 times than the drug alone. Therefore, the new ibuprofen oral solid preparation composition prepared by using poloxamer and hydrophilic polymer at the same time was found to have an excellent bioavailability than the ibuprofen drug itself.

* P <0.05: comparison with data of ibuprofen drug powder

** Mean ± S.E. (n = 5)

Figure 1 shows a SEM photograph of the ibuprofen oral solid preparation composition (Example 8).

Figure 2 shows the ibuprofen concentration curve in plasma after oral administration of ibuprofen oral solid preparation composition (Example 8) and drug powder to mice.

Claims (4)

4-7% by weight of poloxamer, 0.05-0.1% by weight of sodium lauryl sulfate, 20-30% by weight of hydrophilic polymer and 50-75% by weight of ibuprofen as active ingredient, Ibuprofen oral solid preparation composition, characterized in that the hydrophilic polymer is at least one component selected from the group consisting of hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and methyl cellulose. The ibuprofen oral solid preparation composition according to claim 1, wherein the poloxamer is at least one component selected from the group consisting of poloxamer 188 and poloxamer 407. delete (1) dissolving poloxamer, sodium lauryl sulfate and a hydrophilic polymer in water, and (2) suspending the ibuprofen drug in the solution of (1) and then spray drying with warming to 35-45 ° C., A method for producing the ibuprofen oral solid formulation of claim 1.

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