Patent Publication 10-2004-0059695

(19) Korean Intellectual Property Office (KR)

(12) Unexamined Patent Publication (A)

(51) 。Int. Cl. 7 (11) Publication number 10-2004-0059695

A61K 31/7016 (43) Date of publication July 6, 2004

(21) Application number 10-2002-0086100

(22) Date of application December 28, 2002

(71) Applicant Joongeo Pharmaceutical Co., Ltd

698 Sindaebang-dong, Dongjak-gu, Seoul

(72) Inventor Hyunhee Lee

Bldg 101, Bldg. 501, Muhak Apartment, 1531-39, Bongcheon 8-dong, Gwanak-gu, Seoul

Lee Sang-heon

#404, 105-dong, Byucksan e-village, Mangpo Village, Mangpo-dong, Paldal-gu, Suwon-si, Gyeonggi-do

(74) Agent Park Woo

Request for examination: None

(54) Pharmaceutical composition of liquid formulation for oral administration containing lactulose

summary

The present invention relates to a pharmaceutical composition in a liquid dosage form containing lactulose as an active ingredient, and at the same time maintaining the stability of the

preparation and improving the accuracy of the dosage and medication adherence to the patient, chronic constipation patients who need long-term administration or ·
It is an object of the present invention to provide a pharmaceutical composition of a lactulose-containing liquid formulation for oral administration that enables infants to easily take an effective

amount, and the present invention contains 8 to 45% by weight of lactulose. It provides a pharmaceutical composition of a liquid formulation for intravenous lactulose, characterized by one

liquid formulation.

Specification

Detailed description of the invention

Object of the invention

Technology to which the invention belongs and prior art in the field

The present invention relates to a pharmaceutical composition of a liquid formulation containing lactulose as an active ingredient, and more particularly, to prevent deterioration of the formulation

during preservation to maintain formulation stability, and at the same time, patient compliance and accuracy of dose. Patients with chronic constipation who need to take it for a long period of time

· Formulation of lactulose oral liquid formulation that can be easily taken by infants
It is about.

In general, lactulose is used to treat constipation, to treat hepatic coma in chronic portal encephalopathy, and to prevent hepatic coma.
It can be used safely for a long time even for constipation of infants and constipation during pregnancy or after delivery.

Is known as a formulation.

Lactulose is very hygroscopic, so it is easy to dissolve in water and is easy to manufacture, but diluted liquid formulations

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 Patent Publication 10-2004-0059695

There was a problem in that the stability of the formulation was deteriorated, such as a tendency of deterioration. Therefore, most lactulose formulations were prepared and used as syrup in the

state of lactulose concentrate, and powdery or granular formulations have emerged as a result of the recent development of purification methods and the subsequent development of

manufacturing technology for lactulose crystals. .

However, in the case of the lactulose-containing syrup, due to the excessive sweetness and strong viscosity that is difficult to comply with when taking it, the residual feeling of sweetness in the

mouth persists, so patients with chronic constipation and who require long-term use tend to avoid taking it. Therefore, sufficient treatment and prevention effects cannot be expected, and the

accuracy of the dosage is poor due to the strong viscosity. · Treatment

infants of constipation in

There is a problem that it is difficult to administer an effective amount of lactulose, and in the case of lactulose powder formulations, not only does it give a feeling of discomfort attached to the

teeth, but also has the hassle of taking it with milk or soda due to excessive sweetness and strong viscosity There was a problem of taking an excessive amount of water.

Due to the shortcomings of lactulose syrup or powdery formulations as described above, a formulation that can overcome these problems is required. In Korean Patent
Publication No. 2002-0015706, a formulation of foamed chewable tablets using lactulose is a domestic patent. In Publication No. 1997-70010851, a formulation using
lactulose as a jelly type was attempted.

However, in the case of the above-described chewable tablet or jelly type formulation, as in the case of conventional syrup or powder formulations, excessive sweetness and strong
viscosity cause discomfort to adhere to the teeth when taken, so chronic constipation patients require long-term use. Patients have not been able to sufficiently solve conventional
problems such as a tendency to avoid taking.

Accordingly, the present inventors improve compliance with the patient and the accuracy of the dosage to be administered to patients who need long-term administration and

As a result of repeated research on the development of a new formulation that can be easily taken by infants, the pharmaceutical composition of a liquid formulation whose sugar content and
viscosity were reduced by diluting the lactulose concentrate was the average content during storage in stability tests under all conditions. It was confirmed that the formulation stability could be
maintained without showing such a large change, and the present invention was completed based on the results of these studies.

Technical task to be achieved by the invention

Therefore, the present invention maintains the stability of the formulation and at the same time improves the accuracy of medication compliance and dosage for the
patient, · Internal use containing lactulose to allow infants to easily take an effective amount
Its purpose is to provide a pharmaceutical composition in a liquid formulation.

Composition and operation of the invention

In order to achieve the above object, the present invention provides a pharmaceutical composition of a liquid formulation for oral administration of lactulose, characterized by a liquid formulation

containing 8 to 45% by weight of lactulose.

Hereinafter, the present invention will be described in more detail.

In the present invention, by providing a pharmaceutical composition in an oral liquid formulation containing 8 to 45% by weight of lactulose, the formulation stability is excellent, and in the present

invention, the existing lactulose syrup or powder, chewable agent, jelly type Constipation treatment and prevention in chronic constipation patients who require long-term use by providing a

pharmaceutical composition of an oral liquid formulation containing lactulose, which is superior in palatability, such as taste, aroma, and color, unlike the formulation, which improves compliance

with the patient. You can get enough effect. In particular, as a liquid formulation of a certain viscosity is possible,

· Easily and quantitatively for patients who need the accuracy of the dosage, such as infants.
There is an advantage that it can be taken as.

At this time, when the content of lactulose is less than 8% by weight, lactulose is contained in a small amount, so that the sugar content is lowered, as well as the disadvantage of
having to take an excessive amount in order to sufficiently obtain the efficacy effect of lactulose. If the content exceeds 45% by weight, the sugar content becomes large and the
viscosity becomes strong, and even if taken, there are disadvantages such as problems caused by syrups or granules, so it is preferable to contain lactulose within the above
range. More preferably, it is good to contain 13 to 27 parts by weight.

The lactulose may be purified by a conventional method, but a mixture containing unreacted monosaccharides, disaccharides, oligosaccharides, and the like may be used
in the manufacturing process.

In the liquid formulation containing lactulose according to the present invention as an active ingredient, pH may be adjusted by adding a weakly acidic solution or a weakly acidic buffer

solution in order to provide a refreshing sensation and secure formulation stability when taken. At this time, in order to improve drug adherence to the patient, to provide optimal refreshing

sensation without excessive acidity, and to enhance the stability of the formulation.

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It is preferable to adjust the pH to 2.9 to 6, more preferably to 2.98 to 3.2.

The weakly acidic solution may be a solution of a weak acid selected from citric acid, tartaric acid, lactic acid, malic acid, or carbonic acid, and these may be appropriately diluted in
purified water and used.

In addition, the weakly acidic buffer solution contains a weak acid selected from citric acid, tartaric acid, lactic acid, malic acid, or carbonic acid and a base selected from
sodium citrate, sodium tartrate, sodium malate, calcium lactate, sodium lactate, sodium carbonate or sodium hydrogen carbonate. A buffer solution prepared by mixing can
be used.

In the formulation of the lactulose oral liquid formulation according to the present invention, a preservative may be added to maintain the stability of the formulation, and as the
preservatives, paraoxybenzoic acid methyl, paraoxybenzoic acid ethyl, which are usually added during the preparation of liquid formulation formulations. , Paraoxybenzoate propyl,
sodium benzoate may be used. The content of the preferred preservative is from 0.05 to
It is 0.1% by weight.

At this time, preservatives can be added to warm water, if necessary, and then completely dissolved. This is because sodium benzoate is well soluble in water when sodium
benzoate is used as a preservative, but other preservatives are not well soluble in water. . Therefore, it is recommended to first dissolve the preservative in warm water and
then add it.

In addition to the preservative, the formulation of the liquid formulation for oral administration according to the present invention may additionally add a sweetening agent to improve compliance

with medication when taken. The preferred sweetener content is 0.7 to 6% by weight.

The sweetening agent is a sugar sweetener selected from sugar, glucose, starch syrup, fructose, isomerized sugar, maltose, honey, lactose, cryose or
fructooligosaccharide; Sugar alcohol sweeteners selected from chrysiltol, erythritol, sorbitol or maltitol; Somartin, stevia extract,
Non-sugar sweeteners selected from ricyrintic acid or xylitol; Or a synthetic sweetener selected from saccharin, aspartame, alitam, or axulfame;
At least one or more can be selected from and used.

In addition to the above ingredients, the pharmaceutical composition of the liquid formulation for intravenous lactulose according to the present invention includes various
Nutrients, vitamins, electrolysis

Quality, synthetic or natural flavors, colorants, flavor substances (cheese, chocolate, etc.), pectic acid or salts thereof, organic acids, thickeners as protective colloidal substances, preservatives,

Lyserol, alcohol, foaming ingredients for carbonated beverages, etc. can be additionally added, and the content is appropriate as needed.

It can be added by controlling it.

In addition, in the formulation of the liquid formulation for oral administration according to the present invention, natural fruit juice or flesh may be added to further enhance compliance with

medication, and the preferred content is 5 to 20% by weight.

As described above, the formulation of the liquid formulation for oral administration according to the present invention prepared by diluting lactulose in purified water and adding a weakly acidic

solution or a weakly acidic buffer solution, a preservative, a sweetening agent and other additives thereto as necessary is plastic. After filling a container, a glass container or a can container with a

quantity, it can be sterilized and commercialized. If necessary, carbon dioxide gas can be introduced into a commercial product.

As described above, the formulation of the liquid formulation for oral administration according to the present invention in which 8 to 45% by weight of lactulose is contained is preferably taken 1

to 3 times a day based on 75 ml.

Unlike conventional lactulose syrup, powder, chewable, and jelly-type formulations, the formulation of the oral liquid formulation is suitable for chronic constipation patients
who require long-term medication due to improved medication compliance. You can get enough effect. In particular, as a liquid formulation with a certain viscosity is possible,
Easy for patients who need the correct dosage, such as infants
It has the advantage of being able to take it quantitatively. In addition, the formulation of the liquid formulation for oral administration according to the present invention has the advantage of

securing formulation stability.

Hereinafter, the present invention will be described in more detail through the following examples, but this is only presented to aid understanding of the present invention, and the present invention

is not limited thereto.

< Examples 1 to 7>

Add lactulose, citric acid, sodium benzoate, sweeteners such as fructose and xylitol, flavoring, and vitamins in the amounts shown in Table 1 below, and add distilled water
to make the total weight of the mixture 100g. Toulose manufactures an oral solution. The physical properties (sugarity, viscosity, pH) of the prepared liquid formulation are
shown in Table 1 below.

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[Table 1]

Example Example Example Example Example Example Example

division
One 2 3 4 5 6 7

Lactulose (g) 4 8 14 20 32 45 60

Fructose - - 2.5 - - - -

Sweetener Lukos 7.5 - - - 2 - -

(g) Stevia - - - 0.01 - - -

Xylitol - 10.9 - - - - One

Sorbitol - - - - - 1.6 -

Citric acid 240 176 248 - - 270 210

Tartaric acid - - 2.6 - 2.6 - -

Weak acid (mg)
Malic acid 10 5.3 - 10.7 - 6.7 -

Lactic acid - 11 - 200 270 - -

Sodium malate 5 53 - 67 33 30 2

Sodium chloride 2.1 - - 5.2 - 1.3 1.1

Electrolyte (mg)
Potassium chloride - - 4 - 2.7 - 2

Magnesium chloride 1.2 2.6 - 1.3 - - -

Preservative (mg) Sodium benzoate 67 67 67 53 53 53 40

Vitamin (mg) Vitamin C 15 20 33 40 54 62 73

Fragrance(mg) Green grape flavor 0.01 0.05 0.1 0.15 0.2 0.3 0.4

pH 3.05 3.2 2.98 3.8 3.1 2.9 2.96

Sugar content 5.04 10 14 18 41.56 54.06 70.23

Viscosity 2.15 2.23 2.45 2.93 6.88 113.0 201.4

< Experimental Example 1>

The liquid formulations for oral administration prepared in Examples 1 to 7 were left at room temperature for 1 year, at 40°C for 6 months, and at 50°C for 1 month, and then the lactulose

content before and after the test was analyzed by HPLC. At this time, the results are shown in Table 2 below using a refractive index meter (RI detector; Hitachi) as a detector.

[Table 2]

Room temperature 40℃ 50℃

division
Start date 1st year Reduction Start date 6 months Reduction Start date 1st month Reduction

Example 1 100.22% 100.13% 0.09 99.95% 99.44% 0.51 100.06% 99.82% 0.24

Example 2 100.05% 99.68% 0.37 100.08% 100.02% 0.06 99.82% 98.43% 1.39

Example 3 99.83% 99.75 0.08 99.92% 99.37% 0.55 99.94% 97.89% 2.05

Example 4 99.61% 99.46% 0.16 99.68% 99.11% 0.57 99.91% 98.81% 1.13

Example 5 99.75% 99.46% 0.29 100.23% 99.40% 0.83 98.88% 98.07% 0.81

Example 6 100.16% 99.54% 0.62 99.81% 98.77% 1.04 100.45% 99.24% 1.51

Example 7 99.93% 99.65% 0.28 99.34% 98.87% 0.47 100.02% 99.3% 0.72

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As shown in Table 2 above, the liquid formulations of Examples 1 to 7 formulated with lactulose in an oral liquid formulation according to the present invention have an average of 0.5 or less of

the annual average content reduction, even after storage at room temperature, and 40°C. , Even after storage at 50°C for 6 months, it was found to be less than 1% and 2%, respectively,

indicating that the formulation stability was very excellent. This indicates that sufficient constipation treatment and prevention effects can be obtained when the lactulose liquid formulation is

taken.

< Experimental Example 2>

For the liquid formulations prepared in Examples 1 to 7, the sugar content, viscosity, refreshing sensation, and palatability that can improve medication compliance were sensory evaluated in the

following manner, and the results are shown in Table 4 below.

-Sweetness-

47 adult males and 72 adult females take the prepared oral solution, and the taste of the oral solution is classified as'very sweet, sweet, normal, no sweet', and then the number
of people corresponding to each is classified. It is shown in the table.

- Sour taste -

The prepared oral liquid formulation was taken to 47 adult men and 72 adult women. The number of people corresponding to each was indicated in the table
after they were classified as'Soda, Normal, All, and No Sour'.

- bitterness -

The prepared oral solution is taken to 47 adult males and 72 adult females, and the oral solution is classified as'very bitter, bitter, moderate, no bitter taste', and the number
of people corresponding to each is listed in the table. Indicated.

-Excretion point after taking-

The prepared oral solution is taken to 47 adult males and 72 adult females, and the time of excretion 24 hours after taking this oral solution is'within 2 hours, 2 hours to 6 hours, 6
to 24 hours, no effect'. After classifying them, the number of people corresponding to each was indicated in the table.

-Excretion effect after taking-

The prepared oral solution is taken to 47 adult males and 72 adult females, and the excretion effect 24 hours after taking this oral solution is classified into'strong (diarrhea), pleasant stool,
slight taste, and no effect', respectively. The number of people corresponding to is shown in the table.

[Table 3]

division Number of people percentage(%)

male 47 39
gender
female 72 59

more than 3 years 20 16

Duration of constipation 1-3 years 2 2

Less than 1 year 5 4

Intermittent 56 46

[Table 4]

division Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7

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Very sweet 14 16 25 34 72 83 98

sweetness Sweet 6 12 12 38 25 21 15

is average 68 72 72 29 14 7 5

Not sweet 20 13 2 2 One One -

Very 2 - One - - - -

Sour taste sour 5 - - 2 - - -

is average - 4 6 2 - One -

Not sour - - - - - - -

Very write - - One - - - -

bitterness write - - One - - One One

is average One - One One - - One

Have no bitter taste - - - - - - -

Within 2 hours 12 13 30 53 62 81 86
Excretion after taking
2 to 6 hours 25 32 36 27 25 23 24
Point of view
6 to 24 hours 37 24 30 16 18 8 6

no effect 43 39 21 10 5 One -

Strong (diarrhea) 3 15 40 46 53 69 84
excretion

effect
Pleasant 37 53 34 41 42 31 28

Degree Mimi 58 32 21 14 15 7 One

no effect 21 17 12 9 6 2 2

Effects of the Invention

As described above, the present invention is a formulation of a liquid formulation for oral administration that has an appropriate sweet taste and viscosity, unlike conventional lactulose
syrup, powder, chewable, and jelly-type formulations, and maintains formulation stability and improves medication compliance. As it is suitable for chronic constipation patients who need
long-term use, it is possible to sufficiently obtain constipation treatment and preventive effects.
· It is a suitable formulation for infant patients.

(57) Claim

Claim 1.
A pharmaceutical composition of lactulose-containing liquid formulation for oral administration, characterized in that it contains 8 to 45% by weight of lactulose and has a liquid formulation for

internal use.

Claim 2.
The pharmaceutical composition according to claim 1, wherein the pH is adjusted to 2.9-6 by adding a weakly acidic solution or a weakly acidic
buffer solution.

Claim 3.
The pharmaceutical composition according to claim 1 or 2, wherein a preservative is contained in an amount of 0.05 to 0.1% by weight.

Claim 4.
The pharmaceutical composition according to claim 3, wherein a sweetener is contained in an amount of 0.7 to 6% by weight.

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Claim 5.
The pharmaceutical composition of a liquid formulation for oral administration containing lactulose according to claim 4, which contains 5 to 20% by weight of natural fruit juice or flesh.

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