Lactulose oral solution

Abstract

The invention relates to a lactulose oral solution. Specifically, the invention provides the lactulose oral solution, and the lactulose oral solution comprises lactulose, propylene glycol, polyethylene glycol 400, hydroxypropyl methylcellulose, sorbitol, citric acid and water. The lactulose oral solution disclosed by the invention has excellent illumination and high-temperature stability, so that the lactulose oral solution has excellent stability in transportation and storage processes, the transportation and storage cost is reduced, and the quality safety of the lactulose oral solution is improved.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical preparations, in particular to a lactulose oral solution. Background Art

[0002] Lactulose (CAS registration number: 4618-18-2) is often used to relieve constipation and facilitate bowel movements. It can also be used to treat high ammonia levels in the blood caused by liver disease. It can also improve symptoms of abnormal brain function caused by high blood ammonia.

[0003] Among the pharmaceutical preparations of lactulose, lactulose oral solution has the advantages of convenient oral administration and rapid efficacy after administration, and patients have strong compliance with lactulose oral solution. Therefore, lactulose oral solution is widely used in clinical practice. However, the existing lactulose oral solution has the problem of poor light and heat stability, which not only increases the transportation and storage costs of lactulose oral solution, but also easily leads to quality and safety problems of lactulose oral solution during transportation and storage, which easily leads to the emergence of drug safety problems of lactulose oral solution. How to improve the stability of lactulose oral solution is of great significance to reducing transportation and storage costs and improving drug safety.

[0004] Therefore, there is a need in the art to develop a lactulose oral solution with excellent stability. Summary of the invention

[0005] The object of the present invention is to provide a lactulose oral solution, which has excellent stability.

[0006] In a first aspect, the present invention provides a lactulose oral solution, which comprises lactulose, propylene glycol, polyethylene glycol 400, hydroxypropyl methylcellulose, sorbitol, citric acid and water.

[0007] Preferably, the lactulose is 40-60 parts by weight, more preferably 45-55 parts by weight, more preferably 48-52 parts by weight, and most preferably 50 parts by weight.

[0008] Preferably, the content of lactulose is 40-60 g / 100 ml, more preferably 45-55 g / 100 ml, more preferably 48-52 g / 100 ml, and most preferably 50 g / 100 ml.

[0009] Preferably, the propylene glycol is 0.5-2.5 parts by weight, more preferably 1.0-2.0 parts by weight, more preferably 1.3-1.7 parts by weight, and most preferably 1.5 parts by weight.

[0010] Preferably, the content of propylene glycol is 0.5-2.5 g / 100 ml, more preferably 1.0-2.0 g / 100 ml, more preferably 1.3-1.7 g / 100 ml, and most preferably 1.5 g / 100 ml.

[0011] Preferably, the polyethylene glycol 400 is 0.5-1.5 parts by weight, more preferably 0.6-1.0 parts by weight, more preferably 0.7-0.9 parts by weight, and most preferably 0.8 parts by weight.

[0012] Preferably, the content of polyethylene glycol 400 is 0.5-1.5 g / 100 ml, more preferably 0.6-1.0 g / 100 ml, more preferably 0.7-0.9 g / 100 ml, and most preferably 0.8 g / 100 ml.

[0013] Preferably, the amount of the hypromellose is 0.5-2.0 parts by weight, more preferably 0.8-1.6 parts by weight, more preferably 1.0-1.4 parts by weight, and most preferably 1.2 parts by weight.

[0014] Preferably, the content of the hypromellose is 0.5-2.0 g / 100 ml, more preferably 0.8-1.6 g / 100 ml, more preferably 1.0-1.4 g / 100 ml, and most preferably 1.2 g / 100 ml.

[0015] Preferably, the sorbitol is 1.0-3.0 parts by weight, more preferably 1.5-2.5 parts by weight, more preferably 1.8-2.2 parts by weight, and most preferably 2.0 parts by weight.

[0016] Preferably, the content of sorbitol is 1.0-3.0 g / 100 ml, more preferably 1.5-2.5 g / 100 ml, more preferably 1.8-2.2 g / 100 ml, and most preferably 2.0 g / 100 ml.

[0017] Preferably, the citric acid is 0.4-1.0 parts by weight, more preferably 0.4-0.8 parts by weight, more preferably 0.5-0.7 parts by weight, and most preferably 0.6 parts by weight.

[0018] Preferably, the content of citric acid is 0.4-1.0 g / 100 ml, more preferably 0.4-0.8 g / 100 ml, more preferably 0.5-0.7 g / 100 ml, and most preferably 0.6 g / 100 ml.

[0019] Preferably, the water is 80-120 parts by weight, more preferably 90-110 parts by weight, more preferably 95-105 parts by weight, and most preferably 100 parts by weight.

[0020] Preferably, the water comprises purified water.

[0021] Preferably, the lactulose oral solution comprises:

[0022]

[0023] Preferably, the lactulose oral solution comprises:

[0024]

[0025] Preferably, the lactulose oral solution comprises:

[0026]

[0027] Preferably, the lactulose oral solution comprises:

[0028]

[0029] Preferably, the lactulose oral solution comprises:

[0030]

[0031]

[0032] The second aspect of the present invention provides a method for preparing the lactulose oral solution as described in the first aspect of the present invention, wherein the method comprises the steps of:

[0033] The lactulose oral solution is obtained by mixing lactulose, propylene glycol, polyethylene glycol 400, hydroxypropyl methylcellulose, sorbitol, citric acid and water.

[0034] Preferably, the lactulose oral solution is prepared by the following method:

[0035] Take 75-85% of the prescribed amount of water, add propylene glycol and polyethylene glycol 400, stir and mix, add hypromellose, stir and mix, add lactulose, stir and mix, add sorbitol and citric acid, stir and mix, add water to make up to the dispensing volume, filter through a filter membrane, and obtain a lactulose oral solution.

[0036] Preferably, the water comprises boiled and cooled water.

[0037] Preferably, the stirring and mixing temperature is 35-45°C, such as 40°C.

[0038] Preferably, the filtering comprises filtering through 0.45 μm and 0.22 μm microporous membranes in sequence.

[0039] The third aspect of the present invention provides a medicine kit, wherein the medicine kit comprises the lactulose oral solution as described in the first aspect of the present invention.

[0040] Preferably, the medicine box also includes a transparent container (such as a transparent PET bottle)

[0041] Preferably, the lactulose oral solution is packaged in the transparent container.

[0042] In a fourth aspect, the present invention provides a use of the lactulose oral solution as described in the first aspect of the present invention, for preparing a drug for relieving constipation and / or treating hyperammonemia and diseases caused by elevated blood ammonia.

[0043] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form new or preferred technical solutions. DETAILED DESCRIPTION

[0044] The invention discloses a lactulose oral solution, which comprises lactulose, propylene glycol, polyethylene glycol 400, hydroxypropyl methylcellulose, sorbitol, citric acid and water. The lactulose oral solution composed of the specific components of the invention has excellent light and high temperature stability, thus having excellent stability during transportation and storage, reducing transportation and storage costs and improving the quality and safety of the lactulose oral solution.

[0045] the term

[0046] As used herein, the terms "comprise", "include", and "contain" are used interchangeably and include not only closed definitions, but also semi-closed and open definitions. In other words, the terms include "consisting of", "consisting essentially of".

[0047] As used herein, "hypromellose" and "hydroxypropyl methylcellulose" are used interchangeably, and the English name is hypromellose.

[0048] As used herein, "propylene glycol" refers to 1,2-propylene glycol.

[0049] As used herein, "polyethylene glycol 400" is also referred to as PEG400 (polyethylene glycol 400).

[0050] As used herein, the term "PET" refers to polyethylene terephthalate, also known as Poly (ethylene Terephthalate) in English.

[0051] As used herein, the term "parts by weight" may be any fixed weight expressed in milligrams, grams or kilograms (such as 1 mg, 1 g or 1 kg, etc.). For example, a composition consisting of 1 part by weight of component a and 9 parts by weight of component b may be a composition consisting of 1 gram of component a + 9 grams of component b, or 10 grams of component a + 90 grams of component b, etc. In the lactulose oral solution, the percentage content of a component = (parts by weight of the component / sum of the parts by weight of all components) × 100%. For example, in a composition consisting of 1 part by weight of component a and 9 parts by weight of component b, the content of component a is 10%, and the content of component b is 90%.

[0052] Lactulose oral solution

[0053] The lactulose oral solution of the present invention may include (but not limited to) lactulose, propylene glycol, polyethylene glycol 400, hydroxypropyl methylcellulose, sorbitol, citric acid and water.

[0054] In a preferred embodiment of the present invention, the lactulose oral solution comprises:

[0055]

[0056] Preferably, the lactulose oral solution comprises:

[0057]

[0058] Typically, the lactulose oral solution comprises:

[0059]

[0060] Specifically, the lactulose oral solution of the present invention is as described above in the first aspect of the present invention.

[0061] use

[0062] The present invention also provides a use of the lactulose oral solution of the present invention in preparing a medicine for relieving constipation and / or treating hyperammonemia and diseases caused by elevated blood ammonia.

[0063] The main excellent technical effects of the present invention include:

[0064] The invention develops a lactulose oral solution, which has excellent light and high temperature stability, and thus has excellent stability during transportation and storage, reduces transportation and storage costs, and improves the quality and safety of the lactulose oral solution.

[0065] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are usually based on conventional conditions.

[0066] Example 1 Lactulose oral solution

[0067] In this embodiment 1, a lactulose oral solution is prepared. The prescription composition of the lactulose oral solution is shown in Table 1:

[0068] Table 1 Prescription composition of lactulose oral solution

[0069] Components Dosage Lactulose 50g Propylene glycol 1.5g Polyethylene glycol 400 0.8g Hydroxypropyl methylcellulose 1.2g Sorbitol 2.0g Citric acid 0.6g Add purified water Up to 100ml.

[0070] The preparation method of the lactulose oral solution of this embodiment 1 is as follows:

[0071] Take 80% of the prescribed amount of purified water after boiling and cooling, add the prescribed amount of propylene glycol and the prescribed amount of polyethylene glycol 400, stir and mix at 40°C, add the prescribed amount of hydroxypropyl methylcellulose, stir and mix, add the prescribed amount of lactulose, stir and mix, add the prescribed amount of sorbitol and the prescribed amount of citric acid, stir and mix, add boiled and cooled purified water to make up to the dispensing volume, filter through 0.45μm and 0.22μm microporous filter membranes in turn to obtain lactulose oral solution.

[0072] Example 2 Lactulose oral solution

[0073] In this embodiment 2, a lactulose oral solution is prepared. The prescription composition of the lactulose oral solution is shown in Table 2:

[0074] Table 2 Prescription composition of lactulose oral solution

[0075] Components Dosage Lactulose 50g Propylene glycol 1.0g Polyethylene glycol 400 0.8g Hydroxypropyl methylcellulose 0.5g Sorbitol 2.0g Citric acid 0.6g Add purified water Up to 100ml.

[0076] The preparation method of the lactulose oral solution of this embodiment 2 is as follows:

[0077] Take 80% of the prescribed amount of purified water after boiling and cooling, add the prescribed amount of propylene glycol and the prescribed amount of polyethylene glycol 400, stir and mix at 40°C, add the prescribed amount of hydroxypropyl methylcellulose, stir and mix, add the prescribed amount of lactulose, stir and mix, add the prescribed amount of sorbitol and the prescribed amount of citric acid, stir and mix, add boiled and cooled purified water to make up to the dispensing volume, filter through 0.45μm and 0.22μm microporous filter membranes in turn to obtain lactulose oral solution.

[0078] Example 3 Lactulose oral solution

[0079] In this embodiment 3, a lactulose oral solution was prepared. The prescription composition of the lactulose oral solution is shown in Table 3:

[0080] Table 3 Prescription composition of lactulose oral solution

[0081] Components Dosage Lactulose 50 g Polyethylene glycol 400 0.8 g Hydroxypropyl methylcellulose 0.5 g Sorbitol 2.0 g Citric acid 0.6 g Add purified water Up to 100 ml.

[0082] The preparation method of the lactulose oral solution of this embodiment 3 is as follows:

[0083] Take 80% of the prescribed amount of purified water after boiling and cooling, add the prescribed amount of polyethylene glycol 400, stir and mix at 40°C, add the prescribed amount of hydroxypropyl methylcellulose, stir and mix, add the prescribed amount of lactulose, stir and mix, add the prescribed amount of sorbitol and the prescribed amount of citric acid, stir and mix, add boiled and cooled purified water to make up to the dispensing volume, filter through 0.45μm and 0.22μm microporous filter membranes in turn to obtain lactulose oral solution.

[0084] Example 4 Lactulose oral solution

[0085] This Example 4 prepares a lactulose oral solution, and the prescription composition of the lactulose oral solution is shown in Table 4:

[0086] Table 4 Prescription composition of lactulose oral solution

[0087] Components Dosage Lactulose 50 g Propylene glycol 0.8 g Polyethylene glycol 400 0.4 g Hydroxypropyl methylcellulose 1.0 g Sorbitol 2.0 g Citric acid 0.6 g Add purified water Up to 100 ml.

[0088] The preparation method of the lactulose oral solution of this embodiment 4 is as follows:

[0089] Take 80% of the prescribed amount of purified water after boiling and cooling, add the prescribed amount of propylene glycol and the prescribed amount of polyethylene glycol 400, stir and mix at 40°C, add the prescribed amount of hydroxypropyl methylcellulose, stir and mix, add the prescribed amount of lactulose, stir and mix, add the prescribed amount of sorbitol and the prescribed amount of citric acid, stir and mix, add boiled and cooled purified water to make up to the dispensing volume, filter through 0.45μm and 0.22μm microporous filter membranes in turn to obtain lactulose oral solution.

[0090] Stability test

[0091] 1. Investigation on the stability of light factors

[0092] The lactulose oral solution prepared in Example 1-4 and packaged in a transparent PET bottle was placed under illumination conditions (4500 lx, 25°C) for 0 days, 5 days and 10 days, and the appearance of the lactulose oral solution at different time points was examined according to the Chinese Pharmacopoeia Preparation Stability Test Guidelines. The lactulose content (limit of 90%-110%) and the impurities fructose (limit of ≤1.0%), galactose (limit of ≤15.0%), lactose (limit of ≤10%), tagatose (limit of ≤4.0%) and epilactose (limit of ≤10%) of the lactulose oral solution were determined by high performance liquid chromatography. The results of the light stability test of the lactulose oral solution prepared in Example 1-4 are shown in Table 5 below.

[0093] Table 5 Stability test results of lactulose oral solution prepared in Examples 1-4 under illumination conditions (4500 lx, 25°C)

[0094]

[0095] Note: “—” means no measurement is required.

[0096] It can be seen from Table 5 that the lactulose oral solution prepared in Example 1 has excellent light stability, and thus has excellent stability during transportation and storage, reduces transportation and storage costs, and improves the quality and safety of the lactulose oral solution.

[0097] 2. Accelerated stability test

[0098] The lactulose oral solution prepared in Example 1 and packaged in a transparent PET bottle was placed at a temperature of 40±2°C and a relative humidity of RH 75±5% for 0 days, 1, 3 and 6 months. The appearance of the lactulose oral solution at different time points was examined according to the guidelines for the stability test of preparations in the Chinese Pharmacopoeia. The lactulose content (limit of 90%-110%) and the impurities fructose (limit of ≤1.0%), galactose (limit of ≤15.0%), lactose (limit of ≤10%), tagatose (limit of ≤4.0%) and epilactose (limit of ≤10%) of the lactulose oral solution were determined by high performance liquid chromatography. The results of the accelerated stability study of the lactulose oral solution prepared in Example 1 are shown in Table 6 below. Table 6 Stability study results of the lactulose oral solution prepared in Example 1 under accelerated conditions (40±2°C, RH 75±5%)

[0099]

[0100]

[0101] It can be seen from Table 6 that the lactulose oral solution prepared in Example 1 has excellent accelerated stability, and thus has excellent stability during transportation and storage, reduces transportation and storage costs, and improves the quality and safety of the lactulose oral solution.

[0102] The above is an implementation scheme of the present invention designed for a case. It should be pointed out that for ordinary technicians in this technical field, several improvements can be made without departing from the principle of the present invention, and these improvements should also be regarded as the scope of protection of the present invention.

Claims

1. A lactulose oral solution, characterized in that: The lactulose oral solution comprises lactulose, propylene glycol, polyethylene glycol 400, hydroxypropyl methylcellulose, sorbitol, citric acid and water.

2. The lactulose oral solution according to claim 1, characterized in that The lactulose is 40-60 parts by weight, preferably 45-55 parts by weight, more preferably 48-52 parts by weight, and most preferably 50 parts by weight; The propylene glycol is 0.5-2.5 parts by weight, preferably 1.0-2.0 parts by weight, more preferably 1.3-1.7 parts by weight, and most preferably 1.5 parts by weight; The polyethylene glycol 400 is 0.5-1.5 parts by weight, preferably 0.6-1.0 parts by weight, more preferably 0.7-0.9 parts by weight, and most preferably 0.8 parts by weight; The amount of the hypromellose is 0.5-2.0 parts by weight, preferably 0.8-1.6 parts by weight, more preferably 1.0-1.4 parts by weight, and most preferably 1.2 parts by weight; The sorbitol is 1.0-3.0 parts by weight, preferably 1.5-2.5 parts by weight, more preferably 1.8-2.2 parts by weight, and most preferably 2.0 parts by weight; The citric acid is 0.4-1.0 parts by weight, preferably 0.4-0.8 parts by weight, more preferably 0.5-0.7 parts by weight, and most preferably 0.6 parts by weight; and The water is 80-120 parts by weight, preferably 90-110 parts by weight, more preferably 95-105 parts by weight, and most preferably 100 parts by weight.

3. The lactulose oral solution according to claim 1, characterized in that The lactulose oral solution comprises:

4. The lactulose oral solution according to claim 1, characterized in that The lactulose oral solution comprises:

5. The lactulose oral solution according to claim 1, characterized in that The lactulose oral solution comprises:

6. The lactulose oral solution according to claim 1, characterized in that The lactulose oral solution comprises:

7. The lactulose oral solution according to claim 1, characterized in that The lactulose oral solution comprises:

8. A method for preparing the lactulose oral solution according to claim 1, the method comprising the steps of: The lactulose oral solution is obtained by mixing lactulose, propylene glycol, polyethylene glycol 400, hydroxypropyl methylcellulose, sorbitol, citric acid and water.

9. A medicine box, characterized in that: The medicine kit comprises the lactulose oral solution as claimed in claim 1.

10. A use of the lactulose oral solution according to claim 1, characterized in that: Used for preparing medicines for relieving constipation and / or treating hyperammonemia and diseases caused by elevated blood ammonia.

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