KR101431069B1 - Syrup comprising Pelargonium sidoides extract and levodropropizine - Google Patents

Abstract

The invention Pella Konishi Titanium sidoyi des (Pelargonium sidoides ) extract; A syrup containing levodopropegin as an active ingredient, comprising at least 30 w / v% of saccharides, at least 30 w / v% of glycerol; Or a stable syrup without precipitate formation comprising at least 40 w / v% of a mixture of sugars and glycerol.

Description

(Syrup comprising Pelargonium sidoides extract and levodropropizine) containing Pelargonium sidoides extract and levodopropazine

The invention Pella Konishi Titanium sidoyi des (Pelargonium sidoides ) extract and levodoprojin as an active ingredient.

Pelargonium sidoides is a perennial shrub plant, with approximately 80% of the plants distributed in South Africa. The extract extracted from roots of Pella Konishi Titanium sidoyi des (Pelargonium sidoides) is known to be superior in treatment for respiratory system diseases, in particular tuberculosis. The root extract of Pelargonium sidoides has been used in the United States in the 20th century and early on for the treatment of upper respiratory infections such as nasal pills, tonsillitis, venous sinusitis and bronchitis under the trade name Umckaloabo ^TM (Kauffer, HJ (1915) Dental Cosmos 57, 1366). Levodropropizine is a peripheral vasoconstrictor that has low incidence of central nausea (drowsiness) and inhibits inflammation, bronchoconstriction, and mucus hypersecretion. Beta blocker, methylxanthine, mucoadhesive agent, corticosteroid, antibiotic, It is known as a drug that can safely be administered without interaction with other drugs such as antihistamines. Thus, a combination comprising Pelargonium sidoides and levodoprodepine as an active ingredient can be used in combination with cough It is expected to be useful for the treatment of acute chronic infections, especially respiratory diseases such as bronchitis , sinusitis, tonsillitis, and nasopharyngitis, and infectious diseases of the nasopharyngeal region.

Pelargonium sidoides ) and levodoprojin as an active ingredient may be usefully used as pharmaceutical preparations in the form of syrups. Syrup formulations are easy to administer to children or elderly people who lack the ability to swallow tablets, exhibit drug efficacy faster than tablets, and can minimize differences in bioavailability that can be caused by differences in drug solubility in individuals upon tablet administration , There is an advantage that the medicinal effect can be kept constant. In addition, it is possible to drastically improve the bitter taste and unpleasant smell caused by the drug when administered orally, and it is possible to easily administer the drug to children and the elderly as the compliance of the patients is increased.

On the other hand, the present inventors have found that Pelargonium sidoides ) and levodoprojin as an active ingredient, a pharmaceutical composition in the form of a syrup was prepared. Pelargonium sidoides extract and levodoprojin are mixed in an aqueous medium such as distilled water, an unknown precipitate is formed and it is difficult to formulate it. The present inventors conducted an analysis of various pharmaceutical factors in order to develop a pharmaceutical composition in the form of a stable syrup without precipitate formation. As a result, it was found that certain factors, i.e., pH conditions and the content of additives, .

Accordingly, the present invention Pella Konishi Titanium sidoyi des (Pelargonium sidoides ) and levodopropegin as an active ingredient, and to provide a stable syrup formulation free from the formation of precipitates.

According to one aspect of the invention, Pella Konishi Titanium sidoyi des (Pelargonium sidoides ) extract; Levodoprofen; 30 w / v% or more of saccharides; And a pH adjusting agent, is provided.

According to another aspect of the invention, Pella Konishi Titanium sidoyi des (Pelargonium sidoides ) extract; Levodoprofen; Glycerol 30 w / v% or more; And a pH adjusting agent, is provided.

According to a further aspect of the present invention, Pella Konishi Titanium sidoyi des (Pelargonium sidoides) extract; Levodoprofen; 40 w / v% or more of a mixture of saccharide and glycerol; And a pH adjusting agent, is provided.

In the syrup according to the present invention, the content of the saccharide or glycerol is preferably 30 to 80 w / v%, and the content of the mixture of saccharide and glycerol is preferably 40 to 90 w / v%. The saccharide may be at least one selected from the group consisting of sugar, fructose, glucose, lactose, maltose, mannitol, arabitol, erythritol, isomalt, lactitol, maltitol, xylitol, sorbitol and hydrogencarbonate starch hydrolyzate . The pH adjusting agent may be hydrochloric acid or citric acid.

In one embodiment, Pella Konishi Titanium sidoyi des (Pelargonium sidoides ) extract 15.44 w / v%; Levodopropegin 0.6 w / v%; 60 w / v% mixture of white sugar and glycerol; an amount of citric acid for adjustment to pH 3; And a remaining amount of water, is provided. In this embodiment, the mixture of white sugar and glycerol may be a mixture of 30 w / v% of white sugar and 30 w / v% of glycerol.

It has been found by the present invention that, when the pH condition and the content of the additive are adjusted to a certain range, a pharmaceutical composition in the form of a stable syrup can be produced without forming a precipitate. In particular, Pella Swan Stadium sidoyi Death (Pelargonium sidoides ) and levodopropegin , and more than 30 w / v% of white sugar and 30 w / v% or more of glycerol; Or more than 40 w / v% of a mixture of white sugar and glycerol, stable syrup without precipitate formation can be produced.

In this specification, " Pelargonium " sidoides extract "refers to an extract obtained according to a conventional method obtained from Pelargonium sidoides, and includes, for example, an extract obtained according to the method disclosed in Korean Patent No. 896453. The Pelargonium Titanium sidoyi des (Pelargonium sidoides) extract is commercially available (for example, the Republic of Korea Daepyung Co. Ltd.). in the syrup of the present invention, the Pella Konishi Titanium sidoyi des (Pelargonium sidoides) extract is therapeutically Can be used in an effective amount, and can be used, for example, at a concentration of 0.0001 to 10 g / ml, preferably 0.001 to 5 g / ml per unit dosage form.

"Levodropropizine" is a known compound having the structure of the following formula (1) as the (2S) -3- (4-phenylpiperazin-1-yl) propane-1,2-diol. In a syrup according to the present invention, the levodopropezin may be used in a therapeutically effective amount, for example, in an amount of 0.0001 to 10 g / ml, preferably 0.001 to 2 g / ml per unit dosage form, ml. < / RTI >

The invention Pella Konishi Titanium sidoyi des (Pelargonium sidoides ) extract; Levodoprofen; 30 w / v% or more of saccharides; And a pH adjusting agent. The content of the saccharide may be in the range of 30 to 80 w / v%, preferably 30 to 60 w / v%, more preferably 30 to 40 w / v%. The saccharide may be at least one selected from the group consisting of sugar, fructose, glucose, lactose, maltose, mannitol, arabitol, erythritol, isomalt, lactitol, maltitol, xylitol, sorbitol and hydrogencarbonate starch hydrolyzate And preferably, it may be a bag.

The invention also Pella Konishi Titanium sidoyi des (Pelargonium sidoides ) extract; Levodoprofen; Glycerol 30 w / v% or more; And a pH adjusting agent. The content of the glycerol may be in the range of 30 to 80 w / v%, preferably 30 to 60 w / v%, more preferably 30 to 40 w / v%.

The present invention also relates to Pelargonium sidoides extract; Levodoprofen; 40 w / v% or more of a mixture of saccharide and glycerol; And a pH adjusting agent. The content of the mixture of the saccharide and glycerol may be in the range of 40 to 90 w / v%, preferably 60 to 80 w / v%. In the mixture of the saccharide and glycerol, the kinds of saccharides are as described above. In addition, the ratio of saccharide to glycerol is not particularly limited, and can be used, for example, at a weight ratio of 1: 1.

In the syrup of the present invention, the pH adjusting agent may be hydrochloric acid or citric acid, and may be used in an amount suitable for adjusting the pH of the preparation to a pH of 4 or less. Preferably, citric acid can be used.

In one embodiment, Pella Konishi Titanium sidoyi des (Pelargonium sidoides ) extract 15.44 w / v%; Levodopropegin 0.6 w / v%; 60 w / v% mixture of white sugar and glycerol; an amount of citric acid for adjustment to pH 3; And a remaining amount of water, is provided. In this embodiment, the mixture of white sugar and glycerol may be a mixture of 30 w / v% of white sugar and 30 w / v% of glycerol.

Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are for illustrating the present invention, and the scope of the present invention is not limited to these examples.

To see, and the Pella Konishi Titanium sidoyi des (Pelargonium sidoides) used in Example extract Republic of Korea Co. Daepyung Lt; / RTI >

Reference Example . Identification of sediment

Pelargonium sidoides) to an amount effective as a therapeutic of the extract (distilled water, 100 ml of the 15.44 g) and Lebo draw pro precipitate generated when a mixture of effective amounts (0.6 g of distilled water 100 ml as a therapeutically Pidgin) to determine which specifically , A confirmation test was conducted. a pH of 1.2 to 9 under conditions, Pella Konishi help in distilled water 100 ml sidoyi des (Pelargonium 15.44 g and 0.6 g of sidoides extract and levodopropegin, respectively, were dissolved, and the resulting solution was centrifuged and the supernatant and precipitate were separated. The content of levodoprojin in each of the supernatant and the precipitate was analyzed by high performance liquid chromatography (HPLC). The results are shown in Table 1 below.

pH The supernatant (wt%) The precipitate (% by weight) 1.2 98 0.52 4.0 99 0.40 6 97 0.57 8 98 0.56 9 99 0.65

From the results of Table 1, it can be seen that about 97% or more levodopropazine was detected in the supernatant, and a relatively small amount was detected in the precipitate. Thus, the precipitate that occurs during the mixing of the two components is believed to be due mostly from Pella Konishi Titanium sidoyi des (Pelargonium sidoides) extract.

Example  One. pH Evaluation of stability according to

To 60 ml of distilled water was added 0.6 g levodopropegin, stirred for 20 minutes, and then the pH was adjusted from 2 to 9.3 by the addition of citric acid. Pella Konishi helpful in the respective solutions sidoyi des (Pelargonium sidoides ) extract was added to the mixture, and distilled water was added thereto to prepare a syrup having a final volume of 100 ml. Table 2 shows the results of visually confirming whether precipitation of the obtained syrup occurred.

ingredient Content (in 100 ml of distilled water) Levodoprofen 0.6 g 0.6 g 0.6 g 0.6 g 0.6 g 0.6 g 0.6 g 0.6 g 0.6 g 0.6 g Pelagonium sidoides extract 15.44 g 15.44 g 15.44 g 15.44 g 15.44 g 15.44 g 15.44 g 15.44 g 15.44 g 15.44 g Citric acid 1.3 g 1.1 g 1.0 g 0.5 g 0.46 g 0.09 g 0.08 g 0.05 g 0.02 g 0g pH 2 2.5 3 4 5 6 7 8 9 9.3 Whether precipitation occurred Non-sedimentation Non-sedimentation Non-sedimentation Non-sedimentation Sedimentation Sedimentation Sedimentation Sedimentation Sedimentation Sedimentation

As can be seen from the results of Table 2, precipitates did not occur at pH 4 or lower, that is, at pH 2 to 4, but precipitates occurred at pH 5 or higher. Thus, Pella Swan Stadium sidoyi Death (Pelargonium The physical stability of the complex containing sidoides extract and levodoprojin is greatly influenced by the pH and is preferably adjusted to at least pH 4 or less.

Example  2. Evaluation of stability according to syrup additive (glycerol)

Glycerol was added to 20 ml of distilled water at 100 캜, stirred for 20 minutes, and then cooled to about 45 캜 with stirring. 0.6 g of levodopropegin was added, stirred for 20 minutes, and then the pH was adjusted to pH 3 by the addition of citric acid. Pelargonium 15.44 g of sidoides extract was added and stirred for 20 minutes. Then, distilled water was added to the resulting solution while stirring to prepare a syrup having a final volume of 100 ml. The results of visually confirming whether precipitation of the obtained syrup occurred are shown in Table 3 below.

ingredient Content (in 100 ml of distilled water) Levodoprofen 0.6 g 0.6 g 0.6 g 0.6 g 0.6 g 0.6 g 0.6 g 0.6 g 0.6 g 0.6 g 0.6 g 0.6 g Pelagonium sidoides extract 15.44 g 15.44 g 15.44 g 15.44 g 15.44 g 15.44 g 15.44 g 15.44 g 15.44 g 15.44 g 15.44 g 15.44 g Glycerol 2.62 g 10g 15g 20g 25g 30g 35g 40g 45g 50g 55g 60g Citric acid 1.0 g 1.0 g 1.0 g 1.0 g 1.0 g 1.0 g 1.0 g 1.0 g 1.0 g 1.0 g 1.0 g 1.0 g pH 3 3 3 3 3 3 3 3 3 3 3 3 Whether precipitation occurred Sedimentation Sedimentation Sedimentation Sedimentation Sedimentation Non-sedimentation Non-sedimentation Non-sedimentation Non-sedimentation Non-sedimentation Non-sedimentation Non-sedimentation

As can be seen from the results of Table 3, no precipitate was formed and the stability was maintained when the content of glycerol was 30 w / v% or more.

Example  3. Syrup Additives ( White sugar )

White sugar was added to 20 ml of distilled water at 100 캜, stirred for 20 minutes, and then cooled to about 45 캜 with stirring. 0.6 g of levodopropegin was added, stirred for 20 minutes, and then the pH was adjusted to pH 3 by the addition of citric acid. Pelargonium 15.44 g of sidoides extract was added and stirred for 20 minutes. Then, distilled water was added to the resulting solution while stirring to prepare a syrup having a final volume of 100 ml. Table 4 shows the results of visually confirming whether precipitation of the obtained syrup occurred.

ingredient Content (in 100 ml of distilled water) Levodoprofen 0.6 g 0.6 g 0.6 g 0.6 g 0.6 g 0.6 g 0.6 g 0.6 g 0.6 g 0.6 g 0.6 g Pelagonium sidoides extract 15.44 g 15.44 g 15.44 g 15.44 g 15.44 g 15.44 g 15.44 g 15.44 g 15.44 g 15.44 g 15.44 g White sugar 10g 15g 20g 25g 30g 35g 40g 45g 50g 55g 60g Citric acid 1.0 g 1.0 g 1.0 g 1.0 g 1.0 g 1.0 g 1.0 g 1.0 g 1.0 g 1.0 g 1.0 g pH 3 3 3 3 3 3 3 3 3 3 3 Whether precipitation occurred Sedimentation Sedimentation Sedimentation Sedimentation Non-sedimentation Non-sedimentation Non-sedimentation Non-sedimentation Non-sedimentation Non-sedimentation Non-sedimentation

As can be seen from the results of Table 4, no precipitate was formed and the stability was maintained when the content of white sugar was 30 w / v% or more.

Example  4 to 8. Evaluation of stability according to syrup additive (other saccharides)

Saccharide was added to 20 ml of distilled water at 100 ° C, stirred for 20 minutes, and then cooled to about 45 ° C with stirring. 0.6 g of levodopropegin was added, stirred for 20 minutes, and then the pH was adjusted to about pH 3 by the addition of citric acid. Pelargonium 15.44 g of sidoides extract was added and stirred for 20 minutes. Then, distilled water was added to the resulting solution while stirring to prepare a syrup having a final volume of 100 ml. Table 5 shows the result of visually confirming whether precipitation of the obtained syrup occurred.

As can be seen from the results of Table 5, no precipitates were formed and the stability was maintained when the content of saccharides was 30 w / v% or more.

Example  9. Add syrup (glycerol) and pH Evaluation of stability according to

Glycerol was added to 20 ml of distilled water at 100 캜, stirred for 20 minutes, and then cooled to about 45 캜 with stirring. 0.6 g of levodopropegin was added, stirred for 20 minutes, and then the pH was adjusted as shown in Table 6 by adding citric acid. Pelargonium 15.44 g of sidoides extract was added and stirred for 20 minutes. Then, distilled water was added to the resulting solution while stirring to prepare a syrup having a final volume of 100 ml. Table 6 shows the result of visually confirming whether precipitation of the obtained syrup occurred.

ingredient Content (in 100 ml of distilled water) Levodoprofen 0.6 g 0.6 g 0.6 g 0.6 g 0.6 g 0.6 g 0.6 g 0.6 g 0.6 g 0.6 g Pelagonium sidoides extract 15.44 g 15.44 g 15.44 g 15.44 g 15.44 g 15.44 g 15.44 g 15.44 g 15.44 g 15.44 g Glycerol 40g 40g 40g 40g 40g 40g 40g 40g 40g 40g Citric acid 1.3 g 1.1 g 1.0 g 0.5 g 0.46 g 0.09 g 0.08 g 0.05 g 0.02 g 0g pH 2 2.5 3 4 5 6 7 8 9 9.3 Whether precipitation occurred Non-sedimentation Non-sedimentation Non-sedimentation Non-sedimentation Sedimentation Sedimentation Sedimentation Sedimentation Sedimentation Sedimentation

From the results shown in Table 6, it can be seen that, even when the glycerol content is 30 w / v% or more, it is preferable in terms of physical stability that the pH is adjusted to 4 or less, that is, the pH is in the range of 2 to 4.

Example  10. Syrup Additives ( White sugar ) And pH Evaluation of stability according to

White sugar was added to 20 ml of distilled water at 100 캜, stirred for 20 minutes, and then cooled to about 45 캜 with stirring. 0.6 g of levodopropegin was added, stirred for 20 minutes, and then the pH was adjusted as shown in Table 6 by adding citric acid. Pelargonium 15.44 g of sidoides extract was added and stirred for 20 minutes. Then, distilled water was added to the resulting solution while stirring to prepare a syrup having a final volume of 100 ml. Table 7 shows the result of visually confirming whether precipitation of the obtained syrup occurred.

ingredient Content (in 100 ml of distilled water) Levodoprofen 0.6 g 0.6 g 0.6 g 0.6 g 0.6 g 0.6 g 0.6 g 0.6 g 0.6 g 0.6 g Pelagonium sidoides extract 15.44 g 15.44 g 15.44 g 15.44 g 15.44 g 15.44 g 15.44 g 15.44 g 15.44 g 15.44 g White sugar 40g 40g 40g 40g 40g 40g 40g 40g 40g 40g Citric acid 1.3 g 1.1 g 1.0 g 0.5 g 0.46 g 0.09 g 0.08 g 0.05 g 0.02 g 0g pH 2 2.5 3 4 5 6 7 8 9 9.3 Whether precipitation occurred Non-sedimentation Non-sedimentation Non-sedimentation Non-sedimentation Sedimentation Sedimentation Sedimentation Sedimentation Sedimentation Sedimentation

From the results shown in Table 7, it can be seen that it is preferable from the physical stability standpoint that the pH is adjusted to 4 or less, that is, the pH is in the range of 2 to 4, even when the white sugar content is 30 w / v% or more.

Example  11 to 18. Syrup additives (other saccharides) and pH Evaluation of stability according to

Saccharide was added to 20 ml of distilled water at 100 ° C, stirred for 20 minutes, and then cooled to about 45 ° C with stirring. 0.6 g of levodopropegin was added, stirred for 20 minutes, and then the pH was adjusted as shown in Table 8 by adding citric acid. Pella Konishi Titanium sidoyi des (Pelargonium sidoides) was added to extract 15.44 g was prepared in the following, syrup according to the final volume by adding distilled water while stirring the resulting solution to 100 ml and stirred for 20 minutes. Table 8 shows the result of visually confirming whether precipitation of the obtained syrup occurred.

It can be seen from the results of Table 8 that it is preferable in terms of physical stability that the pH is adjusted to 4 or less, that is, the pH is in the range of 2 to 4, even when the content of the saccharide is 30 w / v% or more.

Example  19. Syrup additives (glycerol and White sugar ) And pH Evaluation of stability according to

Glycerol and white sugar were added to 20 ml of distilled water at 100 占 폚, stirred for 20 minutes, and then cooled with stirring at about 45 占 폚. 0.6 g of levodopropegin was added, stirred for 20 minutes, and then the pH was adjusted to about pH 3 by the addition of citric acid. Pelargonium sidoides ) was added and stirred for 20 minutes. Then, distilled water was added to the resulting solution while stirring to prepare a syrup having a final volume of 100 ml. Table 9 shows the results of visually confirming whether precipitation of the obtained syrup occurred.

From the results shown in Table 9, it can be seen that the total content of glycerol and white sugar is preferably adjusted to a range of at least 40 w / v% from the viewpoint of physical stability.

Claims (10)

delete Pelargonium sidoides extract; Levodoprofen; Glycerol 30 w / v% or more; pH adjusting agents; ≪ / RTI > and water. delete delete The syrup of claim 2, wherein the content of glycerol is 30 to 80 w / v%. delete delete The syrup according to claim 2 or 5, wherein the pH adjusting agent is hydrochloric acid or citric acid. delete delete