KR20040059695A - Liquid type pharmaceutical composition containing lactulose - Google Patents

Abstract

PURPOSE: Provided is a pharmaceutical composition of internal liquid formulation which contains lactulose as an active ingredient. The composition maintains stability,and increases medication compliance and the accuracy of medication doses. CONSTITUTION: A pharmaceutical composition of internal liquid formulation containing lactulose is characterized by containing 8-45 wt.% of lactulose. Its pH value is adjusted to 2.9-6 by adding weak acid solution or weak acid buffer. It further contains 0.05-0.1 wt.% of preservative, 0.7-6 wt.% of sweetener and 5-20 wt.% of natural fruit juice or meat.

Description

Pharmaceutical composition of lactulose-containing oral liquid formulation

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 to improve patient compliance and dosage accuracy. The present invention relates to a formulation of a lactulose oral liquid formulation which can be easily taken by chronic constipation patients or infants and toddlers who need to take a long-term dose.

In general, Lactulose is useful for the treatment of constipation, the treatment of hepatic coma in chronic contextual encephalopathy, and the prevention of hepatic coma, and especially for constipation in infants and young children and during constipation during pregnancy or after delivery. Known formulations that can be used.

Lactulose is very hygroscopic and easily dissolved in water and easily prepared, but diluted liquid formulations have a problem of poor formulation stability, such as a tendency of deterioration of the formulation during storage. Therefore, most of the lactulose formulations were prepared and used as lactulose concentrate syrups, and recently, powder or granule formulations have appeared due to the development of purification methods and the development of lactulose crystals.

However, in the case of the syrup containing lactulose, patients who require long-term administration, such as patients with chronic constipation, tend to avoid taking it because of the residual sweetness in the mouth due to excessive sweetness and strong viscosity that are difficult to comply with when taking it. It is difficult to expect sufficient therapeutic and preventive effects, and it is difficult to administer an effective amount to treat constipation in infants and toddlers because the viscosity is strong and the accuracy of dosage is low. In addition to the unpleasant feeling of attachment, there is a problem in that the hassle or excessive water to be taken in milk or soda due to excessive sweetness and strong viscosity.

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

However, in the case of the chewable tablets or jelly-type preparations described above, as in the case of conventional syrups or powdery preparations, they may cause discomfort to the teeth due to excessive sweetness and strong viscosity, and thus require long-term administration such as patients with chronic constipation. The patient has not sufficiently solved the conventional problems, such as the tendency to avoid taking.

Accordingly, the present inventors conducted a study on the development of a new type of formulation that can be easily taken by patients and infants and infants who need to take a long time by improving the dose compliance and dosage accuracy of the patient. Based on the results of these studies, the pharmaceutical composition of the liquid formulation with diluting the Rhose concentrate lowered the sugar and viscosity did not show a significant change during storage in the stability test under all conditions. The invention has been completed.

Accordingly, the present invention improves drug compliance and dosage accuracy of patients while maintaining formulation stability, thereby allowing lactulose to be easily taken in effective amounts for patients with chronic constipation or infants and toddlers who need long-term administration. It is an object to provide a pharmaceutical composition of the containing oral liquid formulation.

In order to achieve the above object, the present invention provides a pharmaceutical composition of a lactulose oral liquid formulation, characterized in that the liquid formulation to be contained 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 of an oral solution formulation containing 8% to 45% by weight of lactulose is excellent in formulation stability, and also in the present invention is a conventional lactulose syrup or powder, chewing agent, jelly type formulation Unlike the pharmaceutical composition of Lactulose-containing oral liquid formulations with excellent taste, flavor, color, etc., it improves compliance with patients and improves the compliance of patients with chronic constipation. Can get enough. In particular, since it is possible to form a liquid of a certain viscosity, there is an advantage that can be easily and quantitatively administered to patients who need the accuracy of the dosage, such as infants and infants.

In this case, when the content of lactulose is less than 8% by weight, a small amount of lactulose is contained, so that the sugar content decreases, and in order to sufficiently obtain the efficacy effect of lactulose, it is necessary to take an excessive amount of lactulose. If the content exceeds 45% by weight, the sugar content is increased and the viscosity is strong, so even if taken, there are disadvantages such as problems caused in syrups or granules, it is preferable to contain lactulose within the above range. More preferably, it is good to contain 13-27 weight part.

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

The formulation of the liquid formulation containing lactulose according to the present invention as an active ingredient may be adjusted to pH by adding a weakly acidic solution or a weakly acidic buffer solution in order to impart a refreshing feeling and to ensure formulation stability. At this time, it is preferable to adjust the pH to 2.9 to 6, and more preferably to pH 2.98 to 3.2 in order to give the optimal refreshing feeling without excessive sour taste and to improve the formulation stability so as to improve the medication compliance to the patient. It is good to adjust.

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 with purified water.

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

The formulation of the lactulose oral liquid formulation according to the present invention may be added with a preservative to maintain formulation stability. The preservative may be paraoxybenzoic acid methyl or paraoxybenzoic acid ethyl, which is usually added during preparation of the liquid formulation formulation. , Paraoxy benzoic acid propyl, sodium benzoate can be used. Preferred content of the preservative is 0.05 to 0.1% by weight.

In this case, the preservative may be added to warm water to be completely dissolved, and then added thereto, since it is well soluble in water when sodium benzoate is used as a preservative, but other preservatives are not soluble in water. Therefore, it is better to dissolve the preservative first in warm water and then add it.

In addition to the preservatives, the preparation of the oral liquid formulation according to the present invention may further include a sweetening agent in order to enhance compliance with the medication. Preferred sweetener content is from 0.7 to 6% by weight.

The sweetening agent includes a sugar sweetener selected from sugar, glucose, syrup, fructose, isomerized sugar, maltose, honey, lactose, chlorose or fructooligosaccharide; Sugar alcohol sweeteners selected from chrysitol, erythritol, sorbitol or maltitol; Non-sugar sweeteners selected from somartin, stevia extract, glycyrrhizin acid or xylitol; Or synthetic sweeteners selected from saccharin, aspartame, alltam or axulfame; At least 1 type or more can be selected and used from etc.

In addition to the components described above, the pharmaceutical composition of the lactulose oral liquid formulation according to the present invention includes various nutrients, vitamins, electrolytes, synthetic or natural flavors, colorants, flavors (such as cheese and chocolate), pectinic acid or salts thereof, organic acids. Thickeners, preservatives, glycerol, alcohols, foaming ingredients for carbonated beverages, and the like, as protective colloidal substances may be further added, and the content thereof may be appropriately adjusted as necessary.

In addition, the formulation of the oral solution formulation according to the present invention may be added with natural juice or flesh to further enhance the drug compliance, the preferred content is 5 to 20% by weight.

As described above, the preparation of the oral liquid formulation 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 sweetener and other additives as necessary is a plastic container. B. After filling the glass container or can container with quantitative amount, it can be sterilized and commercialized. If necessary, carbon dioxide can be introduced into a conventional method for commercialization.

As described above, the formulation of the oral liquid formulation according to the present invention to contain 8 to 45 wt% of lactulose is preferably taken 1 to 3 times per day based on 75 ml.

Unlike conventional lactulose syrups, powders, chewables, and jelly-type preparations, the formulations of the oral liquid formulations are suitable for chronic constipation patients who require long-term administration due to enhanced medication compliance and treatment and prevention of constipation when taken. The effect can be fully obtained. In particular, as a liquid formulation having a certain viscosity is possible, there is an advantage that a patient who needs an accurate dosage such as infant and infant can easily take a quantitative dose. In addition, the formulation of the oral dosage form according to the present invention has the advantage of ensuring formulation stability.

Hereinafter, the present invention will be described in more detail with reference to the following examples, which are only presented to aid the understanding of the present invention, but the present invention is not limited thereto.

<Examples 1 to 7>

Lactulose, citric acid, sodium benzoate, sweeteners, fructose and xylitol, flavors and vitamins were added and mixed with distilled water as shown in the following Table 1, and further distilled water was added so that the total mixture weight was 100 g. Toulose internal preparation liquid was prepared. Physical properties (sugar, viscosity, pH) of the prepared liquid are shown in Table 1 below.

division Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Lactulose (g) 4 8 14 20 32 45 60 Sweetener (g) Fructose - - 2.5 - - - - Glucose 7.5 - - - 2 - - Stevia - - - 0.01 - - - Xylitol - 10.9 - - - - One Sorbitol - - - - - 1.6 - Weak acid (mg) Citric acid 240 176 248 - - 270 210 Tartaric acid - - 2.6 - 2.6 - - Malic acid 10 5.3 - 10.7 - 6.7 - Lactic acid - 11 - 200 270 - - Sodium malate 5 53 - 67 33 30 2 Electrolyte (mg) Sodium chloride 2.1 - - 5.2 - 1.3 1.1 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 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 lactulose content before and after the test was analyzed for 1 year at room temperature, 6 months at 40 ° C., 1 month at 50 ° C., respectively, after preparing the oral solution prepared in Examples 1 to 7 by HPLC. At this time, using a refractive index detector (Hitachi) as a detector, the results are shown in Table 2 below.

division Room temperature 40 ℃ 50 ℃ Start date 1st year Decrease Start date 6 months Decrease Start date 1 month Decrease 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

As shown in Table 2, the liquid formulations of Examples 1 to 7 formulated with lactulose in the form of an oral solution according to the present invention, after storage at room temperature, the average of the amount of decrease in the average content of 1 year is 0.5 or less, 40 ℃ After storage for 6 months at a temperature of 50 ℃, 1%, 2% or less, respectively, it can be confirmed that the formulation stability is very excellent. This suggests that sufficient constipation treatment and prophylactic effect can be obtained by taking the formulation of the lactulose liquid formulation.

Experimental Example 2

The sweetness, viscosity, cooling and palatability of the liquid preparations prepared in Examples 1 to 7, which can enhance medication compliance, were evaluated by the following method, and the results are shown in Table 4 below.

-Sweetness-

The prepared oral solution was taken to 47 adult males and 72 adult females, and the taste of the oral liquid solution was classified as "very sweet, sweet, normal, or no sweetness". Shown in

- Sour taste -

The prepared oral solution is taken to 47 adult males and 72 adult females, and the internal oral liquid is classified as "Let's be very hot. Suppose, normal, not sour." It was.

- bitter -

The prepared oral solution is taken to 47 adult males and 72 adult females, and the internal oral liquid is classified as "very bitter, bitter, normal or bitter", and the number of persons corresponding to each is shown in the table. It was.

-Excretion after taking-

The prepared oral solution was administered to 47 adult males and 72 adult females, and the excretion time was 24 hours after taking the internal oral solution within 2 hours, 2 to 6 hours, 6 to 24 hours, and no effect. After the classification, the number of persons corresponding to each is shown in the table.

-Excretion effect after taking-

The prepared oral solution was taken to 47 adult males and 72 adult females, and after 24 hours of taking the oral solution, the excretory effects were divided into "strong (diarrhea), ecstasy, tasteless, and no effect", respectively. The number of people corresponding to is shown in the table.

division Embroidery percentage(%) gender south 47 39 female 72 59 Constipation Duration more than 3 years 20 16 1 to 3 years 2 2 Less than 1 year 5 4 Intermittent 56 46

division Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 sweetness Very sweet 14 16 25 34 72 83 98 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 - Sour taste Very sour 2 - One - - - - sour 5 - - 2 - - - is average - 4 6 2 - One - Not sour - - - - - - - bitter Write very - - One - - - - write - - One - - One One is average One - One One - - One Not bitter - - - - - - - Excretion after taking Within 2 hours 12 13 30 53 62 81 86 2 to 6 hours 25 32 36 27 25 23 24 6 to 24 hours 37 24 30 16 18 8 6 no effect 43 39 21 10 5 One - Excretion effect Strong (diarrhea) 3 15 40 46 53 69 84 Pleasure 37 53 34 41 42 31 28 Mimi 58 32 21 14 15 7 One no effect 21 17 12 9 6 2 2

As described above, the present invention, unlike conventional lactulose syrups, powders, chewables, jelly-type preparations as a formulation of the oral liquid formulations to have a proper sweetness and viscosity, the formulation stability is maintained and drug compliance is improved. It is suitable for chronic constipation patients who need to take a long time to get enough constipation treatment and preventive effect, and is also suitable for infants and infants who need accurate dosage.

Claims (5)

A pharmaceutical composition of lactulose-containing oral liquid formulation, characterized in that it contains 8 to 45% by weight of lactulose and has a form of an oral liquid formulation. The pharmaceutical composition of the lactulose-containing oral solution formulation according to claim 1, wherein the pH is adjusted to 2.9 to 6 by adding a weakly acidic solution or a weakly acidic buffer solution. The pharmaceutical composition of the lactulose-containing oral liquid formulation according to claim 1 or 2, which contains 0.05 to 0.1% by weight of a preservative. The pharmaceutical composition of the lactulose-containing oral liquid formulation according to claim 3, which contains 0.7 to 6% by weight of a sweetener. The pharmaceutical composition of the lactulose-containing oral liquid formulation according to claim 4, which contains 5 to 20% by weight of natural fruit juice or pulp.