KR101297354B1 - Stable and taste masking syrup composition of transparent solution comprising Dexibuprofen - Google Patents

Abstract

The present invention is characterized by the fact that no deposition, sedimentation or delamination occurs at all during long-term preservation using a minimum of excipients, and efficient use of a small amount of neohesperidine with the stimulating bitterness of dexibuprofen It is to prepare a transparent dexibuprofen syrup having the characteristic of shielding.

Description

Stable and taste masking syrup composition of transparent solution comprising Dexibuprofen

The present invention relates to a transparent oral syrup composition containing dexibuprofen.

Ibuprofen is a representative drug of Non-Steroidal Anti-Inflammatory Drug, which has the effects of analgesic, antipyretic, anti-inflammatory, fast time to reach effective blood concentration, low bioavailability and low price Sun is one of the commonly used antipyretic analgesic anti-inflammatory drugs.

Ibuprofen exists in the racemate which the (S) body and (R) body which are optically active bodies are comprised in the same ratio. Dual (R) forms have no effect, and only (S) forms exhibit efficacy. Therefore, the formulation consisting of optically active agent (S) -Ibuprofenman (dexibuprofen) with pharmacological activity can not only expect a large pharmacological effect with a relatively small dose, but also (S) -Ibuprofenman (dexibuprofen). Pen) has a 50% dose of (R)-ibuprofen and is equivalent or more effective, and compared to ibuprofen, it is known that the pharmacologic effect is rapid due to a shorter time of expression of the medicament.

Dexibuprofen is a representative poorly water-soluble drug having the following structure, white crystalline powder, slightly peculiar smell and bitter taste, and insoluble in water. In order to improve this point and provide adequate bioavailability, much research is being conducted.

[Formula 1]

Dexibuprofen is a representative drug of propionic acid nonsteroidal anti-inflammatory drugs. It inhibits the activity of cyclooxygenase and inhibits the biosynthesis of prostaglandins. It is widely used for the treatment of ankylosing spondylitis and related diseases and for postoperative analgesia and anti-inflammatory.

In addition, dexibuprofen is a white crystalline powder, has a slightly peculiar smell, has a bitter taste with severe throat irritation when dissolved, dissolves in an alkaline solution near the temperature of 50 ℃, acidity (pH) It has the property of solidifying below 3.0. It is also very soluble in alcohol and hardly soluble in water.

To date, preparation of syrups containing dexibuprofen in various forms has been attempted. Dexibuprofen has been manufactured and marketed in the form of tablets or soft capsules to date, and many studies have been conducted on preparations of the transparent solubilized form to be prepared in the present invention.

Various formulation studies have been actively conducted to provide high pharmacological activity by increasing solubility and improving dissolution rate by solubilizing poorly soluble dexibuprofen in water. Typically, solubilization using co-solvent such as ethanol, A method of solubilizing salts such as strong acids or strong bases by attaching ions to poorly soluble materials, or solubilizing a soluble complex by combining a high molecular compound or a ligand has been attempted. There was this.

Korean Patent No. 10-0509432 discloses a method of preparing a syrup by solubilizing dexibuprofen using a dissolving aid, concentrated glycerin and polyoxyl 40 cured castor oil, and adding a sweetening agent to conceal some of the irritating taste. Although disclosed, the taste of polyoxyl 40 cured castor oil added for solubilization is very unpleasant and irritating, and therefore it is advisable to refrain from use in the preparation of oral syrup formulations.

In addition, the Republic of Korea Patent No. 10-0678837 has completed the preparation to improve the stability by removing the glycerin, but the product suspended in an aqueous solution by adding a surfactant and suspending agent to poorly soluble and hydrophobic dexibuprofen oral Because of the viscosity of the suspending agent at the time of taking because it is uncomfortable to take and the taste of the surfactant is not so good that the feeling of rejection. In addition, dexibuprofen is soluble only in alkali, so commercially available suspending agents have low bioavailability in oral cavity or stomach.

On the other hand, neohesperidine dihydrochalcone (C ₂₈ H ₃₆ O ₁₅ , mw 612.60), one of the bioflavonoids used as a sweetener in the present invention is obtained by extracting from the skin or rind of grapefruit or chemically modifying naringin It is 1,500 to 2,000 times sweeter than sugar by weight. In addition, neohesperidin dihydrochalcone is not toxic even if administered to animals for a long time, according to the results of the subchronic toxicity test showed no problem even when ingested at 750 mg / kg / day (BAR Lina et. Al. Food Chem. Toxicol., 7, 500-513, 1990). Aspartame and acesulfame potassium have low sweetness at the beginning of taking as dexbuprofen syrup, and the use of small amount leads to refusal to take infants. Exceeding v% can cause toxicity problems and can be fatal for infants and toddlers.

In the present invention, a sweetener is used in order to effectively mask the pungent and irritating bitterness of the dexibuprofen, and in particular, neohesperidin dihydrochalcone is used as an essential component.

Therefore, the dexibuprofen and neohesperidine dihydrochalcone-containing transparent syrup composition of the present invention shield the unpleasant taste of dexibuprofen and at the same time the stability is confirmed to complete the present invention.

In the present invention, in order to solve the problems described above to improve the dissolution rate and bioabsorption rate, to provide a syrup composition showing the expression of the drug as quickly as possible to the patients.

In addition, the present invention improves the unpleasant taste of the active substance to reduce the rejection of taking infants to increase medication compliance, and provides a stable dexibuprofen syrup composition excellent in stability.

Hereinafter, the technical configuration of the present invention in more detail.

The present invention is dexibuprofen 0.5 to 10.0 w / v%, transparent solution stabilizer 0.25 to 5.0 w / v%, emulsifier 3 to 10 w / v%, neohesperidine dihydrochalcone 0.01 to 1 w / v%, sweetener Clear dexibuprofen syrup composition comprising 20-50 w / v% and purified water 30-70 w / v%.

It provides a transparent dexibuprofen syrup composition, characterized in that it can be included by adding 0.1 to 10 w / v% pH adjuster to the composition.

In another aspect, the present invention provides a transparent dexibuprofen syrup composition comprising an appropriate amount of flavoring agents, preservatives or pigments commonly used in the art to the composition.

The dexibuprofen of the present invention is characterized in that the particles 1 to 20㎛.

The transparent solution stabilizer of the present invention is characterized by using cyclodextrins, steviosides or mixtures thereof, preferably betacyclodextrin.

The emulsifier of the present invention is characterized as using poloxamers, preferably poloxamer 188, poloxamer 407 or a mixture thereof.

The neohesperidine dihydrochalcone of the present invention has a feature of effectively using 0.01 to 1 w / v% to effectively remove the residual feeling when taking the syrup composition.

The sweetener of the present invention is characterized in that it uses white sugar.

The pH adjusting agent of the present invention is characterized by consisting of citrate hydrate, sodium citrate hydrate or a mixture thereof.

In addition, the pH adjusting agent is characterized in that it has a pH of 2.0 to 8.0, preferably pH 3.0 to 5.0.

Fumaric acid may also be used to assist in further masking bitterness.

The preparation method of the dexibuprofen transparent syrup composition of the present invention is as follows, and the present invention will be described in detail below.

Transparent dexibuprofen syrup composition according to the present invention,

a) mixing dexibuprofen, a clear solution stabilizer and neohesperidine dihydrochalcone;

b) adding an emulsifier, a sweetener and a pH adjusting agent to purified water, and then warming to about 90 ° C. while stirring to dissolve while stirring for 1 to 3 hours;

c) adding the mixture of step a) to step b), warming to about 90 ° C. and dissolving with stirring for 1-3 hours;

d) cooling the solution of step c) to about 30 ° C. to 35 ° C .;

It provides a method for producing a transparent dexibuprofen syrup composition comprising a.

The transparent syrup composition of the dexibuprofen of the present invention further comprises adding e.g. a colorant, a preservative or a flavoring agent to the solution of step d), and then mixing it homogeneously.

The composition of the present invention has a feature capable of producing an excellent liquid formulation without using surfactants and suspending agents which have been used in conventional dexibuprofen suspending agents. Therefore, compared to the conventional dexibuprofen suspending agent has excellent fluidity, a refreshing taste and good neck swelling not only improves the convenience and patient compliance of the dose, but also a good biological effect by the rapid drug expression of dexibuprofen It has the characteristic which shows a utilization rate.

The transparent dexibuprofen according to the present invention is prepared with a transparent syrup composition using a minimum of excipients, and has a high stability that does not show any deposition, precipitation, or delamination even during long-term storage.

In addition, the present invention has the feature of effectively shielding the pungent taste of the dexibuprofen with a small amount of neohesperidine.

In addition, the formulation method of the liquid composition is a method well known to those skilled in the art, in addition to the above-mentioned ingredients, flavoring agents, pigments and preservatives, etc. may be used in an appropriate amount according to the user's choice of additives commonly used in the art of the present invention. Purified water may be used to prepare a liquid composition in which the components are dissolved.

The transparent syrup composition containing the dexibuprofen of the present invention improves the unpleasant taste, thereby reducing the objection to taking infants and increases medication compliance, and also prevents the occurrence of deposition, precipitation, and layer separation even during long-term storage. It is possible to obtain a syrup composition with improved homogeneity and improved bioavailability.

Figure 1 shows the dexibuprofen dissolution rate in the composition of Example 1 and pH 1.2 eluting solvent of Comparative Example 1.
Figure 2 shows the dexibuprofen dissolution rate in the composition of Example 1 and pH 6.8 eluting solvent of Comparative Example 1.
Figure 3 shows the dexibuprofen dissolution rate in the composition of Example 1 and the purified water eluting solvent of Comparative Example 1.
Figure 4 shows the results of the layer separation experiment of the transparent syrup composition and the commercial formulation of Example 1 and Comparative Example 1.

Hereinafter, the present invention will be described in detail. However, the following Examples and Experimental Examples are merely illustrative of the present invention, but the content of the present invention is not limited thereto.

Example 1 Preparation of Syrup Composition

5.0 g of poloxamer 188, 30.0 g per bag and a pH adjuster were added to 60 mL of purified water, and then heated to 90 ° C. while stirring for 2 hours. A mixture of 0.6 g of dextrin and 0.2 g of neohesperidine dihydrocalcon was added and dissolved at 90 ° C. for 2 hours, cooled to 30 ° C., and further purified water was added to prepare a total 100 mL solution.

<Example 2 to 6. Preparation of Syrup Composition>

To prepare a oral transparent dexibuprofen syrup 100mL solution by the syrup preparation method of Example 1 with the raw material and the amount shown in Table 1.

Comparative Example 1. Comparative Syrup Composition

Currently available commercially available maxibu pen syrup of Hanmi Pharmaceutical Co., Ltd. was used as Comparative Example 1.

Comparative Examples 2 to 9. Comparative Syrup Composition

To prepare a comparative syrup composition by the syrup preparation method of Example 1 with the raw material and the amount shown in Table 1.

Composition
(g) room
city
Yes
One room
city
Yes
2 room
city
Yes
3 room
city
Yes
4 room
city
Yes
5 room
city
Yes
6 ratio
School
Yes
2 ratio
School
Yes
3 ratio
School
Yes
4 ratio
School
Yes
5 ratio
School
Yes
6 ratio
School
Yes
7 ratio
School
Yes
8 ratio
School
Yes
9 Active ingredient Dexibuprofen
(Particle size
1 to 20 μm)
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2 Emulsifier Phloxamer
188 5 5 5 8 5 5 - 5 5 5 5 5 5 5 Lauryl sulfate
salt - - - - - - 5 - - - - - - - Clear Solution Stabilizer
Beta cyclotextrin
0.6
-
0.6
0.6
One
-
0.6
-
-
0.6
0.6
0.6
0.6
0.6 Stevio
side - 0.6 - - - 5 - - - - - - - - Xylitol - - - - - - - 0.6 - - - - - - Aspartame - - - - - - - - 0.6 - - - - -
Sweetener White sugar 30 30 50 30 25 25 30 30 30 - - 10 60 30 High fructose - - - - - - - - - 30 - - - - D-Sor
Bitol solution - - - - - - - - - - 30 - - - Neohess
Ferridine
Dehydrochalcone
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
- p
H
Regulator
Citrate and Sodium Citrate
enemy
Amount
enemy
Amount
enemy
Amount
enemy
Amount
enemy
Amount
enemy
Amount
enemy
Amount
enemy
Amount
enemy
Amount
enemy
Amount
enemy
Amount
enemy
Amount
enemy
Amount
enemy
Amount Purified water Prepared as a solution in total 100 mL by adding purified water

Experimental Example 1. Precipitation and Appearance Evaluation

The Examples 1 to 6 and Comparative Examples 2 to 9 were visually observed to confirm precipitation and appearance. As a result, no precipitation was observed in Examples 1 to 6 and Comparative Examples 7, 9, and as shown in Table 2, the transparency was confirmed.

division Infiltration and Appearance Evaluation Sedimentation Transparent Example 1 - - Example 2 - - Example 3 - - Example 4 - - Example 5 - - Example 6 - - Comparative Example 2 - + Comparative Example 3 + - Comparative Example 4 + - Comparative Example 5 + - Comparative Example 6 - + Comparative Example 7 - - Comparative Example 8 + + Comparative Example 9 - - -: No precipitation, transparent, +: precipitation, opaque

Experimental Example 2. Sensory Evaluation of Liquid Compositions Prepared According to Table 1

In order to confirm the degree of bitterness of the compositions of Examples 1 to 6, Comparative Examples 1 and 7, 9, 50 subjects having an average body weight of 70 kg were administered to the subjects and sensory evaluation was performed. As shown in Table 3 below, the difference in taste was evaluated by dividing the score into five levels, and the average of the sum of the corresponding scores is shown in Table 4, and the results of the sensory evaluation were prepared in Example 1 according to the present invention. Was found to mask the bitter taste of dexibuprofen, making it easier for the subject to take it.

Degree of taste notation Feeling of taste One There is a very bitter or thin residue. 2 There is a slight bitterness or redness. 3 There is no bitterness and residual feeling. 4 Has no residue and is slightly sweet. 5 Has no residue and is sweet and delicious.

division Evaluation of taste Example 1 4.5 Example 2 2.6 Example 3 3.8 Example 4 2.3 Example 5 3.7 Example 6 4.0 Example 7 3.5 Comparative Example 1 1.4 Comparative Example 7 1.0 Comparative Example 9 1.3

Experimental Example 3. Dissolution Test

Using the compositions of Example 1 and Comparative Example 1, the dissolution test was carried out by the USP dissolution test method and the product dissolution method of megestrol suspension. As the eluate, an aqueous solution of pH 1.2 (artificial gas solution) and pH 6.8 (phosphate solution) and purified water described in the USP elution test method were used. The rate was performed at 25 rpm described in megestrol suspension. At 15, 30, 60, 90 and 120 minutes, 2 mL of the sample was taken and the same amount of eluent was added. Assay conditions, the solution obtained in the above dissolution test was filtered with 0.45㎛ membrane filter was quantitative analysis of dexibuprofen using HPLC. Analytical wavelength was 254 nm, mobile phase was acetonitrile: 1% chloroacetic acid adjusted to pH 3.0 with aqueous ammonia solution ((60:40) mixture, octadecylylated column was used. Experimental results, as can be seen in Figures 1 to 3, it can be seen that the composition of Example 1 of the present invention exhibits a better dissolution rate than the composition of Comparative Example 1.

Experimental Example 4. Stability Test

Example 1 The composition was subjected to stability test and appearance evaluation for 6 months at room temperature (25 ° C.) and accelerated condition (40 ° C., 75% relative humidity) to evaluate precipitation and discoloration. Table 5 (Room temperature 25) ℃ and Table 6 (acceleration conditions, 40 ℃, relative humidity 75%). As can be seen in Table 5 and Table 6, the liquid preparation prepared by the present invention is a color change, layer separation and precipitation phenomenon as a result of the content change test and the flexible material test for 6 months after the preparation of the standard and test method There was no, there was no pH change, the change in content was suitable for the standard range (90 to 110%), and the total flexible material was also found to be less than the standard value (0.3%). Therefore, it can be seen that the liquid formulation prepared by the present invention is a pharmaceutical composition suitable for formulation stability because it is a formulation suitable for the standards and test methods proposed by the Food and Drug Administration.

Test Items
Test period Early 1 month 2 months 4 months 6 months Appearance (discoloration) No change No change No change No change No change Appearance
(Separation / Sedimentation) No change No change No change No change No change pH 4.25 4.21 4.25 4.27 4.23 content 101.0% 101.3% 101.1% 100.8% 101.2% Total flexible material Not detected Not detected Not detected Not detected Not detected

Test Items
Test period Early 1 month 2 months 4 months 6 months Appearance (discoloration) No change No change No change No change No change Appearance
(Separation / Sedimentation) No change No change No change No change No change pH 4.25 4.20 4.26 4.25 4.22 content 101.0% 103.6% 98.5% 99.1% 99.7% Total flexible material Not detected Not detected Not detected Not detected Not detected

Experimental Example 5. Layer Separation Experiment

As a result of observing the Example 1 and Comparative Example 1 compositions stored at room temperature (25 ℃) for 6 months, as shown in Figure 4, the properties and layer separation of the syrup composition of Example 1 is not changed It can be seen, but Comparative Example 1 was confirmed that the layer separation occurred.

Claims (6)

0.5-10.0 w / v% dexibuprofen having an average particle size of 1-20 μm;
0.25-5.0 w / v% of a clear solution stabilizer selected from the group consisting of betacyclodextrin, stevioside and mixtures thereof;
3.0-10.0 w / v% emulsifier selected from the group consisting of poloxamer 188, poloxamer 407, and mixtures thereof;
Neohesperidin dihydrochalcone 0.01-1 w / v%;
20.0 to 50.0 w / v% per bag;
Purified water 30.0 to 70.0 w / v%; And
0.1 to 10.0 w / v% pH adjusting agent;
Transparent dexibuprofen syrup composition, characterized in that pH 2.0 to 8.0. delete The method of claim 1,
Transparent dexibuprofen syrup composition, characterized in that the pH adjusting agent is selected from the group consisting of citrate hydrate, sodium citrate hydrate and mixtures thereof. delete delete As a manufacturing method of the transparent dexibuprofen syrup composition of Claim 1,
Dexibuprofen; Transparent solution stabilizers selected from the group consisting of betacyclodextrin, stevioside and mixtures thereof; And mixing neohesperidin dihydrochalcone (step 1);
Emulsifiers selected from the group consisting of poloxamer 188, poloxamer 407, and mixtures thereof in purified water; PH adjusters selected from the group consisting of citrate hydrate, sodium citrate hydrate and mixtures thereof; Preservatives; And adding sugar and then dissolving by heating while stirring at 70 to 90 ℃ 1 to 3 hours (step 2);
Adding the mixture of step 1 to the solution of step 2 and then dissolving by heating at 70 to 90 ° C. for 1 to 3 hours with stirring (step 3);
Process 3 cooling the solution to 30 to 35 ℃ (step 4);
Method for producing a transparent dexibuprofen syrup composition comprising a.

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