Pharmaceutical composition of amisulpride, suspension and preparation method thereof

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to an amisulpride pharmaceutical composition, an oral suspension prepared from the amisulpride pharmaceutical composition and a corresponding preparation method. The composition disclosed by the invention is mainly composed of amisulpride and polyvinyl alcohol, other pharmaceutical auxiliary materials can be added to prepare an oral suspension, polyvinyl alcohol has the dual effects of modifying taste and assisting suspension, the composition has excellent stability, the bitter taste of amisulpride in a preparation is remarkably improved, and the medication compliance of a patient is improved.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and relates to a pharmaceutical composition of amisulpride, an oral suspension prepared therefrom, and a corresponding preparation method. Background Art

[0002] Amisulpride is an aniline substitute psychotropic sedative that selectively binds to the D2 and D3 dopaminergic receptors of the limbic system, and does not bind to 5-hydroxytryptamine receptors or other histamine receptors, cholinergic receptors, and adrenergic receptors. It is mainly used for the treatment of schizophrenia. As a second-generation antipsychotic drug, amisulpride has unique pharmacological properties, and low-dose amisulpride is significantly more effective than placebo. Currently available drugs include tablets and oral solutions. In clinical applications, tablets and oral solutions are usually used in a single oral form of 100, 200 and 400 mg, up to 1200 mg / day. Compared with tablets, oral liquid preparations solve the problem of poor compliance with dysphagia, and solutions are more convenient to adjust the dosage, thereby meeting the different dosage requirements of patients. However, the active ingredient amisulpride tastes very bitter. Due to the special pathological state of the patient, it is difficult for patients with dysphagia to take a large number of tablets or a certain volume of oral solution, which affects the patient's compliance with medication. Therefore, it is urgent to solve the taste and dosage problems of amisulpride oral preparations.

[0003] Patent CN102600132 A discloses an oral preparation containing amisulpride, which is a cyclodextrin inclusion compound of the active drug amisulpride, and a tablet, capsule or granule is prepared with a pharmaceutically acceptable excipient. The final dosage form of the amisulpride drug combination prepared by this method is a solid, and the tablet or capsule still has the problem of difficulty in swallowing for patients.

[0004] Solian, an oral solution of amisulpride, is available overseas ® The prescription composition includes: active ingredients, antibacterial agents methylparaben, propylparaben, potassium sorbate, flavoring agents saccharin sodium, gluconolactone, sodium gluconate and flavors, and pH regulator hydrochloric acid; from the prescription, it can be seen that the marketed product contains a variety of flavoring agents, among which saccharin sodium is used in a large amount. Some literature points out that saccharin sodium is a food additive synthesized by organic chemical industry. In addition to causing a sweet feeling in the taste, it has no nutritional value to the human body. On the contrary, when more saccharin sodium is consumed, it will affect the normal secretion of gastrointestinal digestive enzymes, reduce the absorption capacity of the small intestine, and reduce appetite. The raw materials for manufacturing saccharin sodium are mainly toluene, chlorosulfonic acid, o-toluidine, etc., and the environment will be seriously polluted during the production process. On the other hand, even if the formula contains a large amount of saccharin sodium, the inventor can feel obvious bitterness in the oral test. If saccharin sodium is removed, the other flavoring ingredients in the commercially available product have no obvious improvement effect on the taste.

[0005] In addition to sodium saccharin, the commonly used flavoring agents in this field also include natural sweeteners such as sucrose and monosaccharide syrup, synthetic sweeteners such as aspartame, and glycerol, sorbitol, mannitol, and stevioside can also be used as sweeteners; and according to the inventor's test, the use of sucrose and monosaccharide syrup as sweeteners requires an amount of more than 30% to achieve the effect of covering the bitterness of amisulpride. Aspartame, within the safe dosage range, can only increase the sweetness of the solution, but cannot cover the bitterness of the drug, and has no significant improvement in palatability; and the use of glycerol, sorbitol, and mannitol, if not used in conjunction with sugars or synthetic sweeteners, has almost no effect on covering the bitterness of amisulpride. The specific results are shown in Table 1 (evaluation criteria: poor < general < good < excellent).

[0006] Table 1 Masking effect of different flavor correctors on the bitter taste of amisulpride

[0007] In addition, solid dispersion technology, ion exchange technology, microencapsulation, and prodrug preparation are also used in this field as means of drug flavor correction. However, the above methods may have certain dosage form limitations, or the technology is relatively complex and not easy to industrialize.

[0008] According to the product specifications and dosage of tablets and oral solutions currently on the market, the conventional dosage of oral solution generally requires 4ml-8ml of administration. At this dosage volume, the bitterness of the drug can be clearly felt. If one wants to reduce the dosage volume, a solution product with a higher concentration specification needs to be prepared. However, due to the solubility limitation of amisulpride, a solution product with a larger specification cannot be prepared. Therefore, the inventors developed amisulpride suspension, and the bitterness of amisulpride is more prominent in the suspension. Summary of the invention

[0009] The purpose of the present invention is to solve the problems of bitter taste and large single-dose volume in oral preparations of amisulpride, and to provide an oral preparation of amisulpride which does not contain other sweeteners or aromatics, can effectively mask the bitter taste of amisulpride, has excellent palatability, has a low dosage volume, and has good patient compliance.

[0010] To achieve the above object, the technical solution of the present invention is: The invention provides an amisulpride-polyvinyl alcohol suspension type pharmaceutical composition. The pharmaceutical composition consists of amisulpride and polyvinyl alcohol and can be used to prepare an amisulpride oral suspension.

[0011] Polyvinyl alcohol is a water-soluble synthetic polymer, with a corresponding molecular weight range of about 20000-200000. The larger the molecular weight, the higher the viscosity. It is mainly used as a film-forming material for oral and external films, a matrix for gels and plasters, a tablet adhesive, a sustained-release and controlled-release skeleton material, a percutaneous absorption preparation material, a capsule of a microcapsule, etc., and is also used in topical medication and ophthalmic preparations. The inventor found in the experiment that amisulpride can be evenly dispersed in a certain concentration of polyvinyl alcohol solution and reach a stable suspension state. It was also unexpectedly found in the experiment that compared with the commonly used suspending agents in other fields, when amisulpride and polyvinyl alcohol form a pharmaceutical composition, polyvinyl alcohol can also play a significant masking effect on the bitterness of amisulpride while acting as a suspending agent. It can also have a good taste masking effect when no other sweeteners or aromatics are added. At the same dosage, the single administration volume can be reduced, further improving the compliance of the patient.

[0012] According to the embodiments of the present invention, the inventors used suspending agents commonly used in the field to prepare compositions in a certain proportion, and compared the taste-masking effects on the bitter taste of amisulpride through oral tests.

[0013] Experimental method: Invite experimenters to taste each test group, with 10 points as the basic score, and deduct points according to the degree of bitterness tasted, with each point as one level, and calculate the total score. The specific results are shown in Table 2.

[0014] Table 2 Masking effect of polyvinyl alcohol and different suspending agents on the bitter taste of amisulpride

[0015] From the above results, it can be seen that other commonly used suspending agents such as xanthan gum and sodium carboxymethyl cellulose cannot effectively mask the bitterness of amisulpride. The addition of polyvinyl alcohol has a significant effect on masking the bitterness of amisulpride. Therefore, in addition to being a suspending agent, the main function of polyvinyl alcohol in the pharmaceutical composition of amisulpride is to serve as a flavoring agent.

[0016] Specifically, in the amisulpride-polyvinyl alcohol suspension pharmaceutical composition, the amount of amisulpride used is 100-250 mg / ml, and the amount of polyvinyl alcohol used is 0.3-0.8 mg / ml.

[0017] In certain preferred embodiments, the amount of amisulpine used is 150-250 mg / ml, and the amount of polyvinyl alcohol used is in the range of 0.3-0.5 mg / ml.

[0018] Preferably, the specification of the amisulpride oral suspension is 200 mg / ml.

[0019] In certain embodiments, the pharmaceutical composition disclosed in the present invention further comprises a pharmaceutical excipient that can be added to prepare an oral suspension, and the pharmaceutical excipient is selected from one or more of a thickener, an antibacterial agent, a sweetener, a flavor, a pH adjuster, and purified water; Specifically, the thickener is selected from carboxymethyl cellulose, hypromellose, polyethylene glycol 400, and propylene glycol, and the content is 0.01-0.1% by w / v; The antibacterial agent is selected from methylparaben, ethylparaben, propylparaben, potassium sorbate, sorbic acid, sodium benzoate, and the content is 0.01-0.5% by w / v; The sweetener is selected from fructose, saccharin sodium, monosaccharide syrup, sucralose, aspartame, stevioside, glucose, sodium gluconate, gluconolactone, and the content is 0.01-10% by w / v; The flavor is selected from strawberry banana, vanilla flavor, caramel flavor, brown sugar flavor, maple syrup flavor, chocolate flavor, raspberry flavor, and sweet orange flavor, and the content is 0.01-0.2% by w / v; The pH adjuster is selected from hydrochloric acid, citric acid, sodium hydroxide, sodium citrate, various phosphate buffers and mixtures thereof.

[0020] In certain embodiments, the inventors experimentally determined the sedimentation volume ratio of amisulpride-polyvinyl alcohol pharmaceutical composition at different polyvinyl alcohol dosages; Sedimentation volume ratio test method: Use a stoppered measuring cylinder to measure 50 ml of the test sample, stopper it tightly, shake it vigorously for 1 minute, record the initial height H0 of the suspension, let it stand for 3 hours, record the final height H of the suspension, and calculate according to the following formula: sedimentation volume ratio = H / H0. The results are shown in Table 3.

[0021] Table 3 Sedimentation volume ratio of the composition at different polyvinyl alcohol dosages

[0022] As an oral suspension product, the sedimentation volume ratio should not be less than 0.90. From the results in the above table, it can be seen that when the dosage of polyvinyl alcohol is 0.3-1.0 mg / ml, the sedimentation volume ratio of the composition meets the requirements.

[0023] The present invention also provides a method for preparing an oral suspension containing an amisulpride-polyvinyl alcohol pharmaceutical composition, which comprises: heating purified water to 70-90°C, adding polyvinyl alcohol to completely dissolve it; cooling to 30-50°C, adding xanthan gum, adding amisulpride to uniformly disperse it, adding other adjuvants that can be added to dissolve or disperse it, and finally adjusting the pH value of the solution to 4.0-8.0. 90 ≤100μm.

[0024] Further, in certain preferred embodiments, the particle size D of amisulpride is 90≤60μm, better sedimentation volume ratio.

[0025] In certain more preferred embodiments, the particle size D of amisulpride is 90 The particle size of amisulpride oral suspension is 30-60 μm, and the sedimentation volume ratio of the prepared amisulpride oral suspension is optimal.

[0026] Table 4 Sedimentation volume ratio of compositions prepared with different amisulpride particle sizes

[0027] The inventors used different amounts of amisulpride and polyvinyl alcohol, and other additives to prepare amisulpride oral suspension. The detailed prescription is shown in Examples 1-8. It is compared with the oral liquid product Solian ® (Example 9), oral test evaluation was conducted, and the average score of the scores given by different personnel was calculated. See Table 5 below for details.

[0028] Table 5 Evaluation results of palatability of amisulpride suspensions with different prescriptions

[0029] The results of the tasting experiment show that at a concentration of 200 mg / ml, the best taste is achieved when the amount of polyvinyl alcohol added is 0.3-0.5 mg / ml, and when the amount of polyvinyl alcohol is 0.5 mg / ml, the preparations with concentrations of 150 mg / ml and 250 mg / ml also have a good taste. On this basis, other sweeteners and fragrances can be added to increase the sweetness and aromatic smell of the preparation while masking the bitterness, thereby further improving the palatability of the suspension.

[0030] The oral suspensions prepared in Examples 1-8 and the commercially available oral solution in Example 9 were subjected to stability tests, and the data are shown in Table 6. From the results in Table 6, we can see that the properties, contents and related substances of the oral suspensions in Examples 1-8 did not change significantly after being placed under accelerated test conditions for 6 months, indicating that the amisulpride oral suspension of the present invention has good drug stability.

[0031] The amisulpride-polyvinyl alcohol pharmaceutical composition and suspension thereof described in the invention, polyvinyl alcohol has the dual effects of a flavor corrective and a suspending agent, and within the preferred dosage range, when no other sweeteners or aromatics are added, it can have a good taste masking effect for amisulpride at a concentration greater than 100 mg / ml, can effectively mask the bitter taste of amisulpride, and has excellent palatability. Taking the preferred specification of 200 mg / ml in the invention as an example, according to the conventional clinical dosage of 400 mg of amisulpride, the single dosage volume is only 2 ml, which is significantly reduced compared with the single dosage of 4 ml of the commercially available 100 mg / ml concentration specification, and the patient compliance is good. DETAILED DESCRIPTION

[0032] The present invention will be further described below in conjunction with the embodiments.

[0033] Embodiment 1: Amisulpride oral suspension prescription: Name of raw materials and dosage Amisulpride 150g Polyvinyl alcohol 0.5g Methylparaben 0.2g Propylparaben 0.1g Batch 1000ml Preparation process: Weigh purified water into a beaker, heat in a water bath to 80°C, add methylparaben and stir until dissolved, add propylparaben and stir until dissolved, add polyvinyl alcohol and stir until dissolved, cool to 30-50°C. Add amisulpride and disperse evenly, adjust pH to 4.0-8.0 with hydrochloric acid, and make up to 1000ml.

[0034] Embodiment 2: Amisulpride oral suspension prescription: Name of raw materials and dosage Amisulpride 200g Polyvinyl alcohol 0.5g Methylparaben 0.2g Propylparaben 0.1g Batch 1000ml Preparation process: Same as that of Example 1.

[0035] Embodiment 3: Amisulpride oral suspension prescription: Name of raw materials and dosage Amisulpride 250g Polyvinyl alcohol 0.5g Methylparaben 0.2g Propylparaben 0.1g Batch 1000ml Preparation process: Same as that of Example 1.

[0036] Embodiment 4: Amisulpride oral suspension prescription: Name of raw materials and dosage Amisulpride 200g Polyvinyl alcohol 0.1g Methylparaben 0.2g Propylparaben 0.1g Batch 1000ml Preparation process: Same as that of Example 1.

[0037] Embodiment 5: Amisulpride oral suspension prescription: Name of raw materials and dosage Amisulpride 200g Polyvinyl alcohol 0.3g Methylparaben 0.2g Propylparaben 0.1g Batch 1000ml Preparation process: Same as that of Example 1.

[0038] Embodiment 6: Amisulpride oral suspension prescription: Name of raw materials and dosage Amisulpride 200g Polyvinyl alcohol 0.8g Methylparaben 0.2g Propylparaben 0.1g Batch 1000ml Preparation process: Same as that of Example 1.

[0039] Embodiment 7: Amisulpride oral suspension prescription: Name of raw materials and dosage Amisulpride 200g Polyvinyl alcohol 1.0g Methylparaben 0.2g Propylparaben 0.1g Batch 1000ml Preparation process: Same as that of Example 1.

[0040] Embodiment 8: Amisulpride oral suspension prescription: Name of raw materials and dosage Amisulpride 200g Polyvinyl alcohol 0.5g Sucralose 2g Methylparaben 0.2g Propylparaben 0.1g Strawberry flavor 0.5g Batch 1000ml Preparation process: Weigh purified water into a beaker, heat in a water bath to 80°C, add methylparaben and stir until dissolved, add propylparaben and stir until dissolved, add polyvinyl alcohol and stir until dissolved, cool to 30-50°C. Add sucralose and stir until dissolved, add amisulpride and disperse evenly, adjust pH to 4.0-8.0 with hydrochloric acid. Add strawberry essence and stir evenly, and dilute to 1000ml.

[0041] Example 9: Solian, an oral solution of amisulpride marketed overseas ®, manufacturer: Sanofi-AventisFrance, specification 100mg / ml.

[0042] The amisulpride oral suspensions in Examples 1-8 and the commercially available amisulpride oral solution in Example 9 were placed in a constant temperature and humidity chamber at 40°C and 75% relative humidity for 6 months, and their properties, contents and related substances were tested. The results are shown in Table 6: Table 6 Amisulpride suspension accelerated test results

[0043]

Claims

1. An amisulpride-polyvinyl alcohol suspension pharmaceutical composition, characterized in that The medicine composition mainly consists of amisulpride and polyvinyl alcohol. The dosage of amisulpride is 150-250 mg / ml, and the dosage of polyvinyl alcohol is 0.3-0.8 mg / ml.

2. An amisulpride-polyvinyl alcohol suspension pharmaceutical composition according to claim 1, characterized in that: The dosage of amisulpine is 200 mg / ml, and the dosage of polyvinyl alcohol is 0.3-0.5 mg / ml.

3. An amisulpride-polyvinyl alcohol suspension pharmaceutical composition according to claim 1 or 2, characterized in that: The pharmaceutical composition described herein also includes addible pharmaceutical excipients.

4. The amisulpride-polyvinyl alcohol suspension pharmaceutical composition according to claim 3, characterized in that: The addible pharmaceutical excipients are selected from one or more of thickeners, antibacterial agents, sweeteners, flavors, pH regulators, and purified water.

5. An amisulpride-polyvinyl alcohol suspension pharmaceutical composition according to claim 4, characterized in that: The thickener is selected from carboxymethyl cellulose, hypromellose, polyethylene glycol 400, and propylene glycol, and its content is 0.01-0.1% by w / v.

6. The amisulpride-polyvinyl alcohol suspension pharmaceutical composition according to claim 4, characterized in that: The antibacterial agent is selected from methylparaben, ethylparaben, propylparaben, potassium sorbate, sorbic acid, and sodium benzoate, and the content is 0.01-0.5% by w / v.

7. The amisulpride-polyvinyl alcohol suspension pharmaceutical composition according to claim 4, characterized in that: The sweetener is selected from fructose, saccharin sodium, monosyrup, sucralose, aspartame, stevioside, glucose, sodium gluconate, and gluconolactone, and the content is 0.01-10% by w / v; the flavor is selected from strawberry and banana, vanilla flavor, caramel flavor, brown sugar flavor, maple syrup flavor, chocolate flavor, raspberry flavor, and sweet orange flavor, and the content is 0.01-0.2% by w / v.

8. An amisulpride-polyvinyl alcohol suspension pharmaceutical composition according to claim 4, characterized in that: The pH regulator is selected from hydrochloric acid, citric acid, sodium hydroxide, sodium citrate, various phosphate buffers and mixtures thereof.

9. The amisulpride-polyvinyl alcohol suspension pharmaceutical composition according to claim 1, characterized in that: Amisulpride particle size distribution D 90 30~60μm.

10. An amisulpride-polyvinyl alcohol suspension pharmaceutical composition according to any one of claims 1 to 9, characterized in that: The preparation method of the pharmaceutical composition is as follows: heating purified water to 70-90°C, adding polyvinyl alcohol to completely dissolve it; cooling to 30-50°C, adding amisulpride to evenly disperse it, adding other addible auxiliary materials to dissolve or disperse them, and finally adjusting the pH value of the solution to 4.0-8.0.

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