Citric acid pentoxyverine slow-release dry suspension with taste masking effect and preparation method of citric acid pentoxyverine slow-release dry suspension

Abstract

The invention discloses a pentoxyverine citrate sustained-release dry suspension with a taste-masking effect and a preparation method thereof, and relates to the technical field of medicines, the sustained-release dry suspension comprises pentoxyverine citrate taste-masking sustained-release pellets, a suspending aid, a sweetening agent, a bacteriostatic agent and an aromatic; the preparation method comprises the following steps: firstly, preparing the pentoxyverine citrate taste-masking sustained-release pellets, and then uniformly mixing the pentoxyverine citrate taste-masking sustained-release pellets, the suspending aid, the sweetening agent, the bacteriostatic agent and the aromatic. By adopting the sustained-release framework material, the sustained-release effect is achieved, the medicine taking frequency is reduced, and the medicine taking compliance of a patient is improved.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and particularly relates to a pentoxyverine citrate sustained-release dry suspension with taste-masking effect and a preparation method thereof. Background Art

[0002] Pentoxeverine citrate is a white or off-white crystalline or pelletized powder; it is odorless, bitter, and easily soluble in water. It is a non-addictive central antitussive drug that can selectively act directly on the cough center to block the cough reflex. Large doses can relax spasmodic bronchial smooth muscles, thus having both central and peripheral antitussive effects. The intensity of its antitussive effect is about 1 / 3 of that of codeine. The effect of a single dose can last for 4 to 6 hours, and the half-life of the drug is 2 to 3 hours. It is suitable for non-sputum dry cough and whooping cough caused by upper respiratory tract infection, and its efficacy in children is better than that in adults.

[0003] Pentoxeverine citrate was developed by the Belgian United Chemical Company in 1956 and began to be produced in China in 1962. The current marketed preparations include tablets, syrups, pills and orally disintegrating tablets. The commercially available preparations are mainly pentoxeverine citrate tablets, with a specification of 25 mg. Adults take one tablet at a time, 3 to 4 times a day, and children over 5 years old take 6.25 mg to 12.5 mg at a time, 2 to 3 times a day. Because its efficacy in children is better than that in adults, but there is no specification specifically for children, the commercially available tablets can only be divided. After division, there is not only the problem of unevenness, but also the sugar coating film will be damaged to expose the exposed surface, resulting in a poor taste. In addition, there is a common problem of difficulty in swallowing tablets, which causes its defects in children's administration and the defect of frequent administration. The raw material itself has a strong tendency to crystallize. After being prepared into a suspension, precipitation and poor dispersion effect may occur during the placement process. Therefore, it is urgent to develop a pentoxyverine citrate preparation that has a good taste, is effective, convenient and suitable for children.

[0004] Compared with other drug delivery systems, sustained-release suspensions have the following advantages: ① Large doses of drugs can be made into liquid preparations before use, which have good fluidity and are convenient for dose division; ② They have a large distribution area in the gastrointestinal tract, rapid absorption, relatively stable blood drug concentration, high bioavailability, reduced frequency of administration, and good compliance; ③ The drug release system is a multi-unit microcapsule, and the in vivo behavior of the drug release system is less affected by the gastric emptying rate, with small individual differences and less irritation to the gastrointestinal tract; ④ Defects in the preparation of individual microcapsules or powders will not have a serious impact on the drug release behavior of the entire preparation, so the drug release pattern has good reproducibility; ⑤ Liquid drugs are easy to swallow and are suitable for young children, the elderly and patients with dysphagia.

[0005] CN 116492307 A discloses a pentoxyverine citrate tablet and a preparation method thereof, aiming to solve the problems of sticking, poor hardness, uneven mixing, long coating disintegration time, etc., but the dosage form is still a sugar-coated tablet, the sugar-coating process is cumbersome, and the sugar-coated tablet is difficult to split. After splitting, the raw materials on the exposed surface are exposed, resulting in a poor taste, which poses a challenge to children's medication compliance.

[0006] CN 104434789 B discloses a method for preparing pentoxyverine citrate syrup, which utilizes a solubilizing agent to improve the solubility of pentoxyverine citrate, and only adds sucrose and a sweetener for aroma, resulting in a sweet and bitter taste, which cannot completely cover up the bitterness of pentoxyverine citrate, and is a liquid preparation, which is inconvenient to carry.

[0007] CN 115813886 B discloses a pentoxyverine citrate oral film and a preparation method thereof. Aiming at the problem that the raw material drug has a strong tendency to crystallize, the high drug loading and suitable performance of the pentoxyverine citrate oral film are achieved by compounding two film materials, PVA and sodium alginate. However, the characteristics of this dosage form are that although it is convenient to carry and transport, easy to divide the dose, disintegration is an important way for its rapid release, and it is difficult to avoid the discomfort caused by the taste of the drug. Only by using sweeteners for fragrance, it is also impossible to completely cover up the bitterness of pentoxyverine citrate, and the oral film has a certain hygroscopicity. The film needs to be packaged independently, and a new production line needs to be set up, the equipment is expensive, and the packaging investment is large. Summary of the invention

[0008] In view of the above problems, the present invention provides a pentoxyverine citrate sustained-release dry suspension with taste-masking effect and a preparation method thereof.

[0009] The present invention discloses a pentoxyverine citrate sustained-release dry suspension with taste-masking effect, wherein the dry suspension comprises pentoxyverine citrate taste-masking sustained-release micropellets, a suspending agent, a sweetener, an antibacterial agent and a fragrance;

[0010] Wherein, the weight proportions of the components of the dry suspension are as follows:

[0011] Pentotheline citrate taste-masked sustained-release pellets: 90%-97%

[0012] Suspending agent: 0.5%-3%

[0013] Sweetener: 0.05%-0.5%

[0014] Antibacterial agent: 0.1%-1%

[0015] Fragrance: 0.5%-3%.

[0016] Furthermore, the pentoxyverine citrate taste-masked sustained-release micropellets contain the active ingredient pentoxyverine citrate, excipients, adhesives, sustained-release skeleton materials and coating materials.

[0017] Furthermore, the formulation of the taste-masked pentoxyverine citrate sustained-release microcapsules is composed of 10-12% pentoxyverine citrate, 45-47% excipient, 0.1-0.3% binder, 22-24% sustained-release skeleton material and 17-19% coating material.

[0018] Furthermore, the formulation of the taste-masked pentoxyverine citrate sustained-release microcapsules is composed of 11.6% pentoxyverine citrate, 46.3% excipient, 0.2% binder, 23.1% sustained-release skeleton material and 18.8% coating material.

[0019] Furthermore, the pentoxyverine citrate taste-masked sustained-release micropellets are composed of drug-containing micropellets with sustained-release effect, an isolation layer, and a taste-masking coating layer from the inside to the outside.

[0020] Furthermore, the isolation material in the isolation layer is one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, and methyl cellulose, and the isolation layer accounts for 3%-10% of the weight of the entire sustained-release pellets.

[0021] Furthermore, the taste-masking coating layer is composed of a film-forming material, a plasticizer and a pore-forming agent, and the taste-masking coating layer accounts for 5%-30% of the weight of the entire sustained-release microcapsule; the film-forming material is ethyl cellulose or acrylic resin; the plasticizer is one or more of stearic acid, polyethylene glycol, triethyl citrate, and dibutyl phthalate; the pore-forming agent is one or more of lactose, povidone, polyethylene glycol, and sodium dodecyl sulfate.

[0022] Furthermore, the excipient is silicified microcrystalline cellulose; the binder is one or more of hydroxypropyl cellulose, starch slurry, povidone, and hydroxypropyl methylcellulose; and the skeleton material is one or more of hydroxypropyl methylcellulose, ethyl cellulose, and glyceryl monostearate.

[0023] Furthermore, the suspending agent is one or more of xanthan gum, sodium carboxymethylcellulose, tragacanth gum, and sodium alginate; the sweetener is one or more of aspartame, stevioside, saccharin sodium, and neotame; the antibacterial agent is one or both of sodium benzoate and potassium sorbate; and the fragrance is one or more of banana flavor, orange flavor, and strawberry flavor.

[0024] A method for preparing a pentoxyverine citrate sustained-release dry suspension having a taste-masking effect according to the present invention, the preparation method is as follows:

[0025] (1) Preparation of taste-masked pentoxyverine citrate sustained-release micropellets: The pentoxyverine citrate micropellets are prepared by extrusion spheronization or fluidized bed coating;

[0026] (2) Evenly mix the pentoxyverine citrate taste-masked sustained-release micropellets, suspending agent, sweetener, antibacterial agent and aromatic agent to obtain a product.

[0027] Compared with the prior art, the present invention has the following advantages:

[0028] 1. By adopting sustained-release skeleton materials, a sustained-release effect is achieved, the number of medications is reduced, and the patient's medication compliance is improved.

[0029] 2. The taste of the preparation is further improved by masking the coating and adding sweeteners to the dry suspension. The smell is improved by adding fragrances, which is convenient for children to take. In view of the problem that the API has a strong tendency to crystallize, is easy to precipitate and settle during the storage process after being prepared into a suspension, and has a poor dispersion effect, the porous structure of the excipient silicified microcrystalline cellulose is used to adsorb and disperse the API, inhibit its crystallization and precipitation, and achieve the expected dispersion effect.

[0030] 3. The dry suspension of the present invention can be prepared immediately upon use, thus avoiding the problem of inconvenience in carrying liquid preparations.

[0031] 4. The dosage can be divided according to the minimum dosage for children to avoid overdose and ensure the safety of children's medication.

[0032] 5. The drug release system is a multi-unit microcapsule. The in vivo behavior of the drug release system is less affected by the gastric emptying rate and has small individual differences. It has less irritation to the gastrointestinal tract. Defects in the preparation of individual microcapsules will not have a serious impact on the drug release behavior of the entire preparation, so its drug release pattern is reproducible.

[0033] 6. In the treatment of dry cough without sputum and whooping cough caused by upper respiratory tract infection, the pentoxyverine citrate of the present invention is evenly dispersed in a sustained-release skeleton material and coated with a taste-masking coating. When taken, water is added to achieve a good sustained-release effect, reduce the number of medications, stabilize blood drug concentrations, and mask the bitterness of the raw materials, thereby improving patients' medication compliance. The product is easy to transport and carry, and is suitable for industrial-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 The release curves of Examples 1-3 and Comparative Example 2 in a pH 4.5 medium are shown. DETAILED DESCRIPTION

[0035] In order to make the objectives, technical solutions and advantages of the embodiments of the present invention more clearly understood, the spirit of the contents disclosed by the present invention will be described in detail below. After understanding the embodiments of the contents of the present invention, any technician in the relevant technical field can change and modify them according to the techniques taught by the contents of the present invention without departing from the spirit and scope of the contents of the present invention.

[0036] The exemplary embodiments of the present invention and the description thereof are used to explain the present invention but are not intended to limit the present invention.

[0037] Example 1. Pentotheline citrate sustained-release dry suspension and preparation method thereof

[0038]

[0039] Preparation process:

[0040] a. Preparation of drug-containing sustained-release pellets

[0041] The prescribed amount of pentoxyverine citrate API, silicified microcrystalline cellulose and hypromellose K15 were placed in a multi-directional motion mixer at a speed of 10 rpm and mixed for 30 min to prepare a mixed material, polyvidone was dissolved in water to prepare a 5% aqueous solution, the preliminarily mixed material was placed in an extrusion spheronizer with a mesh size of 1 mm, an extrusion speed of 20 rpm, a spheronization speed of 100 rpm, a fluidized bed inlet temperature of 50-60°C, an exhaust temperature of 35-45°C, and a material temperature of 40-50°C for drying until the moisture content of the pellets was less than 3%, thereby preparing drug-containing sustained-release pellets;

[0042] b. Preparation of isolated pellets

[0043] Dissolve the prescribed amount of Hydroxypropyl Methylcellulose E5 in 630g of purified water, stir continuously to completely dissolve it, prepare a 10% concentration of isolation layer coating solution, use fluidized bed bottom spraying method, inlet air temperature 50-60℃, exhaust air temperature 35-45℃, material temperature 40-50℃, inlet air volume 0.8-1.6m3 / min / kg, coating liquid speed 5-15g / min / kg, atomizing gas pressure 1.5-2bar. Stop coating when the coating weight gain reaches 7%, continue drying in the fluidized bed for 20min until the moisture content is less than 3%, and prepare pentoxyverine citrate isolation micropellets;

[0044] c. Preparation of taste-masked coated sustained-release pellets

[0045] Take a portion of water, add sodium lauryl sulfate, stearic acid and Eudragit EPO, and homogenize with a high shear homogenizer for 30 minutes until a clear colloidal solution is formed. Use the fluidized bed bottom spray method to coat the coating liquid on the isolation micropellets. The inlet air temperature is 30-50℃, the exhaust air temperature is 25-30℃, the material temperature is 25-30℃, and the inlet air volume is 0.7-1.4m 3 / min / kg, coating liquid speed 5-15g / min / kg, atomizing gas pressure 1.5-2bar. Stop coating when coating weight gain reaches 20%, continue drying for 30min, and obtain taste-masked coated sustained-release pellets;

[0046] d. Preparation of dry suspension

[0047] Evenly mix the drug-containing micropellets with the prescribed amount of xanthan gum, stevioside, sodium benzoate and banana powder flavor, and put them into a bottle.

[0048] Examples 2-3 and Comparative Examples 1-4 were prepared according to the process of Example 1. The weight units in the following table are (mg).

[0049]

[0050]

[0051] Taste and smell evaluation

[0052] 10 volunteers were selected, half male and half female, and rinsed their mouths with warm water three times before evaluation. A unit dose of dry suspension was taken and placed in a clean small cup, and 20 ml of warm boiled water was added to prepare a suspension, which was kept for 10 seconds after entering the mouth. Pentotheline citrate equivalent to the content in the unit dose was weighed into a small cup, and warm boiled water was also added to prepare a suspension as a control. The smell and taste of each embodiment, comparative example and control were evaluated.

[0053] The score for aroma was 1, for no odor was 2, and for odor was 3; for taste, sweetness was 1, slightly sweet was 2, not bitter was 3, slightly bitter was 4, bitter was 5, and very bitter was 6. The results are shown in the table below:

[0054] Taste and odor ratings of the sustained-release dry suspensions of Example 1 and Comparative Examples 1-3

[0055]

[0056]

[0057] As can be seen from the above table, the odor and taste of the sustained-release dry suspensions of Examples 1-3 and Comparative Examples 1-3 are improved. Comparative Example 1 uses mannitol as an excipient, the pellets have poor roundness, and there are coating defects. Although sweeteners are added, they are still slightly bitter; Comparative Example 2 does not add sweeteners and fragrances, has no peculiar smell, and is not bitter; Comparative Example 3 has a fragrance and is not bitter; Comparative Example 4 does not add fragrance and has a small coating weight gain, has no fragrance, has a peculiar smell, and is slightly bitter.

[0058] Sedimentation volume ratio and redispersibility

[0059] Add water to the sample and shake it as the test sample. Use a stoppered measuring cylinder to measure 50 ml of the test sample, stopper it tightly, shake it vigorously for 1 minute, and record the initial height H0 of the suspension. Let it stand for 3 hours, and record the final height H of the suspension. Calculate it according to the following formula: sedimentation volume ratio = H / H0. It should be evenly dispersed, and the sedimentation volume ratio should not be less than 0.90.

[0060] The 100 ml stoppered measuring cylinder containing the suspension was rotated 180 degrees, inverted once and stopped for 5 seconds, which was counted as one shaking. The suspension that had been placed for several days was inverted and shaken to redisperse into a uniform system, and the number of shaking times was recorded. The fewer the shaking times, the easier it is to disperse the suspension, and the better the redispersibility. The redispersibility of Examples 1-3 and Comparative Examples 1-4 was checked with good, good, fair, and poor evaluation.

[0061]

[0062]

[0063] In Comparative Example 1, mannitol is used as the excipient, and the amount of suspending agent is consistent with that in Example 1, but the sedimentation volume ratio does not meet the requirements, and the redispersibility is poor. After the liquid is prepared, it can be seen that the raw material is precipitated and precipitated at the bottom of the bottle. In Comparative Example 3, the amount of suspending agent is small, the sedimentation volume ratio does not meet the requirements, and the redispersibility is poor. The remaining comparative examples and embodiments all meet the requirements of the suspension.

[0064] Release determination

[0065] Take this product, according to the dissolution method (paddle method), use 900ml pH4.5 phosphate buffer as the dissolution medium, the speed is 50 revolutions per minute, operate according to the law, and filter the solution at the specified time points (1h, 2h, 4h, 6h, 8h, 10h, 12h, 24h), discard at least 10ml of the initial filtrate, accurately measure the appropriate amount of the subsequent filtrate, add water to dilute to make a solution containing 11μg per 1ml, as the test solution. In addition, accurately weigh 22mg of the pentoxyverine citrate reference substance that has been pre-dried at 60℃ under reduced pressure for 4 hours with phosphorus pentoxide, place it in a 100ml volumetric flask, add water to dissolve and dilute to the scale, shake well, accurately measure 5ml, place it in a 100ml volumetric flask, add water to dilute to the scale, shake well, as the reference solution. Accurately measure 100 μl of each of the above two solutions, inject them into the liquid chromatograph, and record the chromatogram; calculate the dissolution amount of each tablet by the peak area according to the external standard method.

[0066] The release rate of Examples 1-3 and Comparative Example 2 was measured.

[0067]

[0068] The in vitro release curves of Examples 1-3 and Comparative Example 2 are shown in Figure 1 As can be seen from the figure, Examples 1-3 all have good sustained-release effects. Comparative Example 2, since there is no sustained-release skeleton material in the prescription, almost all of the dissolved in 2 hours, there is no sustained-release effect.

Claims

1. A pentoxyverine citrate sustained-release dry suspension having a taste-masking effect, characterized in that The dry suspension comprises pentoxyverine citrate taste-masking sustained-release pellets, a suspending agent, a sweetener, an antibacterial agent and a fragrance; Wherein, the weight proportions of the components of the dry suspension are as follows: Pentotheline citrate taste-masked sustained-release pellets: 90%-97% Suspending agent: 0.5%-3% Sweetener: 0.05%-0.5% Antibacterial agent: 0.1%-1% Fragrance: 0.5%-3%.

2. The pentoxyverine citrate sustained-release dry suspension with taste-masking effect according to claim 1, characterized in that The pentoxyverine citrate taste-masked sustained-release micropellets contain active ingredient pentoxyverine citrate, excipients, adhesives, sustained-release skeleton materials and coating materials.

3. The pentoxyverine citrate sustained-release dry suspension with taste-masking effect according to claim 1, characterized in that The prescription composition of the pentoxyverine citrate taste-masked sustained-release micropellets is 10-12% of pentoxyverine citrate, 45-47% of excipients, 0.1-0.3% of binder, 22-24% of sustained-release skeleton material and 17-19% of coating material.

4. The pentoxyverine citrate sustained-release dry suspension with taste-masking effect according to claim 3, characterized in that The prescription composition of the pentoxyverine citrate taste-masked sustained-release micropellets is 11.6% of pentoxyverine citrate, 46.3% of excipients, 0.2% of binder, 23.1% of sustained-release skeleton material and 18.8% of coating material.

5. The pentoxyverine citrate sustained-release dry suspension with taste-masking effect according to claim 1, 2, 3 or 4, characterized in that The pentoxyverine citrate taste-masked sustained-release micropellets are composed of drug-containing micropellets with sustained-release effect, an isolation layer, and a taste-masking coating layer from the inside to the outside.

6. The pentoxyverine citrate sustained-release dry suspension with taste-masking effect according to claim 5, characterized in that The isolation material in the isolation layer is one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose and methyl cellulose, and the isolation layer accounts for 3%-10% of the weight of the entire sustained-release pellet.

7. The pentoxyverine citrate sustained-release dry suspension with taste-masking effect according to claim 5, characterized in that The taste-masking coating layer is composed of a film-forming material, a plasticizer and a pore-forming agent, and the taste-masking coating layer accounts for 5%-30% of the weight of the entire sustained-release micropill; the film-forming material is ethyl cellulose or acrylic resin; the plasticizer is one or more of stearic acid, polyethylene glycol, triethyl citrate, and dibutyl phthalate; the pore-forming agent is one or more of lactose, povidone, polyethylene glycol, and sodium dodecyl sulfate.

8. The pentoxyverine citrate sustained-release dry suspension with taste-masking effect according to claim 2, 3 or 4, characterized in that The excipient is silicified microcrystalline cellulose; the binder is one or more of hydroxypropyl cellulose, starch slurry, povidone, and hypromellose; and the skeleton material is one or more of hypromellose, ethyl cellulose, and glyceryl monostearate.

9. The pentoxyverine citrate sustained-release dry suspension with taste-masking effect according to claim 1, characterized in that The suspending agent is one or more of xanthan gum, sodium carboxymethylcellulose, tragacanth gum, and sodium alginate; the sweetener is one or more of aspartame, stevioside, saccharin sodium, and neotame; the antibacterial agent is one or both of sodium benzoate and potassium sorbate; and the fragrance is one or more of banana flavor, orange flavor, and strawberry flavor.

10. A method for preparing a pentoxyverine citrate sustained-release dry suspension with taste-masking effect as claimed in claim 1, 2, 3 or 4, characterized in that The preparation method is as follows: (1) Preparation of taste-masked pentoxyverine citrate sustained-release micropellets: The pentoxyverine citrate micropellets were prepared by extrusion spheronization or fluidized bed coating; (2) Evenly mix the pentoxyverine citrate taste-masked sustained-release micropellets, suspending agent, sweetener, antibacterial agent and aromatic agent to obtain a product.

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