CN115501190A

CN115501190A - Spirolactone taste-masking dry suspension for children and preparation method thereof

Info

Publication number: CN115501190A
Application number: CN202211406632.9A
Authority: CN
Inventors: 杨子毅; 林霞; 王永庆; 李成蹊; 盛利娟; 王宏民
Original assignee: Jiangnan University
Current assignee: Jiangnan University
Priority date: 2022-11-10
Filing date: 2022-11-10
Publication date: 2022-12-23
Anticipated expiration: 2042-11-10
Also published as: CN115501190B

Abstract

The invention relates to the field of pharmaceutical preparations, and discloses a spironolactone taste-masking dry suspension for children and a preparation method thereof. The dry suspension contains spironolactone microspheres, a suspending agent, a flocculating agent, a wetting agent and a filling agent; the spironolactone microspheres contain spironolactone and acrylic resin IV; the particle size of the spironolactone microspheres is less than 150 mu m; the weight ratio of spironolactone to acrylic resin IV in the raw materials for preparing the spironolactone microspheres is 1:2-9. The spironolactone taste-masking dry suspension for children can effectively mask the bitterness of a medicine, is not gritty when being suspended in water for taking, and can improve the medication compliance of children patients.

Description

Spirolactone taste-masking dry suspension for children and preparation method thereof

Technical Field

The invention relates to the field of pharmaceutical preparations, in particular to a spironolactone taste-masking dry suspension for children and a preparation method thereof.

Background

Hypertension is one of the main factors causing cardiovascular and cerebrovascular diseases, obviously increases the risk of target organ damage such as coronary heart disease, chronic renal insufficiency and the like, and reduces the life quality of patients. Hypertension is not only present among adults, but children are also suffering from hypertension. The hypertension of children seriously affects the physical and mental health of children and has serious adverse effects on the kidney, the cardiovascular and cerebrovascular systems and the like of children patients.

Clinically, childhood hypertension is divided into primary and secondary types according to the cause of the disease. Hypertension in children is mostly secondary hypertension caused by some underlying disease, for example, renal parenchymal hypertension caused by diseases such as acute and chronic glomerulonephritis and congenital renal dysplasia, renal vascular hypertension caused by congenital renal artery stenosis, and the like. However, children have a low rate of finding hypertension due to unclear self-perception, less routine blood pressure measurement and insignificant clinical symptoms. The relevance between the hypertension of children and the hypertension of adults is strong, and the method has an important prediction value on the hypertension of adults. If children with continuously high blood pressure are not intervened in time, adult hypertension may develop, and target organs such as heart, kidney and the like of patients are injured early. If the early stage of the disease is discovered and the treatment and control are carried out in time, the incidence rate of the essential hypertension and other cardiovascular diseases of the infant after the adult can be greatly reduced.

In the year of 1964, the number of the main raw materials, spironolactone is used for the first time in the treatment of infantile diseases. Since then, spironolactone has been used to treat childhood hypertension, acute cerebral edema, acute cardiac edema, bronchopulmonary dysplasia, and childhood congestive heart failure, among others. The clinical administration dosage of spironolactone for children and infants is about 1-3 mg/kg, and the spironolactone preparation on the market at home is tablets and capsules with the specification of 20mg and cannot meet the dosage requirements of children patients at different ages, so that the spironolactone tablets or capsules on the market are mostly used in divided doses in pediatrics.

At present, most domestic hospitals grind spironolactone tablets into powder for subpackage, namely, firstly grind the tablets into fine powder, evenly divide the powder into a plurality of equal parts according to dosage requirements, and then add water or syrup to prepare a liquid preparation suitable for children or infants to take. Although the grinding and subpackaging solve the problem of clinical divided dose administration, a series of problems still exist: (1) the dosage accuracy is difficult to ensure, and the potential safety hazard of drug treatment exists. Because the dosage of spironolactone for children is small, a pharmacist needs to divide one spironolactone tablet into 10 parts or more, inaccurate dosage subpackage is easy to cause, and even if the experienced pharmacist carries out tablet dosage work, the relative standard deviation of the weight difference of the ground powder subpackage is still large and is about 12.76-34.68 percent; in addition, spironolactone is insoluble in water, and the traditional milled water dispersion is difficult to ensure that the medicine is uniformly dispersed, so that inaccurate dosage is easy to cause. (2) The compliance with the medication is poor. After being ground, spironolactone tablets have bad smell and bitter taste, the ground materials have large particle size and obvious gritty feeling, and the drug compliance of children patients is poor. (3) The operation is complicated, the pharmacist needs to individually dose the children patients with different ages, weights and diseases, and the clinical medication is inconvenient.

Therefore, the development of a spironolactone taste masking preparation which can accurately divide the dose and has stable quality and is suitable for children and infants is urgently needed, and the accuracy of the dose and the safety of the administration of the medicine for children patients are ensured.

Disclosure of Invention

The invention aims to solve the problems of difficulty in ensuring dosage accuracy, poor medication compliance, inconvenience in clinical medication and the like in the prior art, and provides a spironolactone taste-masking dry suspension for children.

In order to achieve the above object, the present invention provides a spironolactone taste-masking dry suspension for children, which comprises spironolactone microspheres, a suspending agent, a flocculating agent, a wetting agent and a filler;

the spironolactone microspheres contain spironolactone and acrylic resin IV; the particle size of the spironolactone microspheres is less than 150 mu m;

the weight ratio of spironolactone to acrylic resin IV in the raw materials for preparing the spironolactone microspheres is 1:2-9.

Preferably, the dry suspension comprises 69-75 wt% of spironolactone microspheres, 3-5 wt% of a suspending agent, 5-7 wt% of a flocculating agent, 8-12 wt% of a wetting agent and 1-10 wt% of a filling agent, based on the total weight of the dry suspension taken as 100 wt%.

In a second aspect, the invention provides a preparation method of a spironolactone taste-masking dry suspension for children, which comprises the following steps:

s1: preparation of spironolactone microspheres:

(1) Mixing spironolactone, acrylic resin IV and an organic solvent to obtain an oil phase;

(2) Mixing an emulsifier and water to obtain a water phase;

(3) Dripping the oil phase obtained in the step (1) into the water phase obtained in the step (2) under stirring at the stirring speed of 800-8000r/min, and continuing stirring after dripping is finished to obtain O/W emulsion;

(4) Removing the organic solvent in the O/W emulsion, then washing with water, mixing the washed product with a mannitol aqueous solution, and then freeze-drying to obtain spironolactone microspheres;

wherein in the step (1), the weight ratio of spironolactone to acrylic resin IV is 1:2-9

S2: preparing a dry suspension:

respectively pulverizing suspending agent, flocculant, wetting agent and filler, and sieving; sieving spironolactone microspheres; and then mixing the screened spironolactone microspheres, the suspending agent, the flocculating agent, the wetting agent and the filling agent to obtain the dry suspension.

Preferably, in step S2, the dry suspension contains 69 to 75 wt% of spironolactone microspheres, 3 to 5 wt% of suspending agent, 5 to 7 wt% of flocculating agent, 8 to 12 wt% of wetting agent and 1 to 10 wt% of filler, based on the total weight of the dry suspension taken as 100 wt%.

Preferably, the mesh number of the screen used in the screening in step S2 is 40 to 100 mesh.

Preferably, in step (1), the concentration of acrylic resin IV in the oil phase is 0.1-0.2g/mL.

Preferably, in step (2), the emulsifier in the aqueous phase is present in a concentration of 0.05 to 1% by weight.

Preferably, the organic solvent is selected from dichloromethane and/or ethyl acetate;

preferably, the emulsifier is selected from polyvinyl alcohol, poloxamer 188 or polysorbate 80.

Preferably, in step (3), the volume ratio of the oil phase to the water phase is 1:5-15.

Preferably, in the step (4), the concentration of mannitol in the mannitol aqueous solution is 0.5 to 3 wt%.

The spironolactone taste-masking dry suspension provided by the invention can accurately divide the dose, has stable quality, is suitable for children and infants to take, and can ensure the accuracy of the dose and the safety of the drug administration of the children patients.

Compared with the prior art, the invention has the beneficial effects that:

(1) According to the invention, the stomach-soluble high polymer material is used as a carrier, the spironolactone is prepared into microspheres in advance, the stomach-soluble high polymer material is insoluble in water, the drug can be effectively prevented from being dissolved in water in the medicine taking process, the prepared spironolactone taste-masking dry suspension for children is placed in drinking water for 30min, the drug release degree is less than 0.5%, the drug bitterness can be effectively masked, and the drug compliance is improved.

(2) The spironolactone taste-masking dry suspension for children prepared by the invention, the particle diameter D of the spironolactone taste-masking microspheres for children ₁₀₀ Less than 150 mu m, has no gritty feeling when being suspended in water for taking, and can improve the medication compliance of children patients.

(3) The spironolactone taste-masking dry suspension for children prepared by the invention is suspended into water for taking before use, and compared with the existing commercially available tablets which are ground, subpackaged and re-suspended, the spironolactone taste-masking dry suspension for children has the advantages that the medicine is more uniformly dispersed in water, and the accurate dosage is easy.

Detailed Description

The following describes in detail specific embodiments of the present invention. It should be understood that the detailed description and specific examples, while indicating the present invention, are given by way of illustration and explanation only, not limitation.

The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and these ranges or values should be understood to encompass values close to these ranges or values. For numerical ranges, each range between its endpoints and individual point values, and each individual point value can be combined with each other to give one or more new numerical ranges, and such numerical ranges should be construed as specifically disclosed herein.

The invention provides a spironolactone taste-masking dry suspension for children, which contains spironolactone microspheres, a suspending agent, a flocculating agent, a wetting agent and a filling agent;

the spironolactone microspheres contain spironolactone and acrylic resin IV; the particle diameter D of the spironolactone microspheres ₁₀₀ Less than 150 μm; further preferably, the particle diameter D of the spironolactone microspheres ₁₀₀ Less than 80 μm;

In a preferred embodiment, the particle size D of the spironolactone microspheres ₁₀ Is 2-50 μm; further preferably, the particle size D of the spironolactone microspheres ₁₀ Is 10-15 μm.

In a preferred embodiment, the particle size D of the spironolactone microspheres ₅₀ 5-90 μm; further preferably, the particle size D of the spironolactone microspheres ₅₀ Is 15-35 μm.

In a preferred embodiment, the particle size D of the spironolactone microspheres ₉₀ 10-125 μm; further preferably, the particle size D of the spironolactone microspheres ₉₀ Is 25-65 μm.

In a specific embodiment, the weight ratio of spironolactone to acrylic resin IV in the raw materials for preparing the spironolactone microspheres can be 1:2, 3:7, 1.

In a specific embodiment of the present invention, the dry suspension comprises 72 wt% of spironolactone microspheres, 4 wt% of suspending agent, 6 wt% of flocculating agent, 10 wt% of wetting agent, and 8 wt% of filler, based on the total weight of the dry suspension taken as 100 wt%.

Preferably, the suspending agent is selected from sodium carboxymethylcellulose or xanthan gum.

Preferably, the flocculating agent is selected from citrate or tartrate.

Preferably, the wetting agent is selected from poloxamer 188.

Preferably, the filler is selected from sucrose, lactose, mannitol or maltitol.

s1: preparation of spironolactone microspheres:

(2) Mixing an emulsifier and water to obtain a water phase;

(4) Removing the organic solvent in the O/W emulsion, then washing with water, mixing the washing product with a mannitol aqueous solution, and then freeze-drying to obtain spironolactone microspheres;

wherein, in the step (1), the weight ratio of spironolactone to acrylic resin IV is 1:2-9;

s2: preparing a dry suspension:

In a preferred embodiment, in step S2, the dry suspension contains 69 to 75 wt% of spironolactone microspheres, 3 to 5 wt% of a suspending agent, 5 to 7 wt% of a flocculating agent, 8 to 12 wt% of a wetting agent, and 1 to 10 wt% of a filler, based on the total weight of the dry suspension taken as 100 wt%.

In particular embodiments, the spironolactone microspheres may be present in the dry suspension in an amount of 69, 70, 71, 72, 73, 74, or 75 wt%; the suspending agent may be present in an amount of 3 wt%, 4 wt% or 5 wt%; the flocculant may be present in an amount of 5 wt%, 6 wt% or 7 wt%; the content of wetting agent may be 8 wt%, 9 wt%, 10 wt%, 11 wt% or 12 wt%; the filler may be present in an amount of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 wt%.

In order to further improve the uniform dispersion of the dry suspension in water, in step S2, the suspending agent, the flocculating agent, the wetting agent and the filler are respectively crushed and sieved, the spironolactone microspheres are sieved, and undersize is taken out and then mixed.

In a preferred embodiment, the mesh size of the screen used in the screening in step S2 is 40 to 100 mesh. Specifically, the mesh number may be 40 mesh, 50 mesh, 60 mesh, 80 mesh or 100 mesh. The spironolactone microspheres, the suspending agent, the flocculating agent, the wetting agent and the filling agent are sieved by using a screen with the same mesh number.

In the method of the present invention, preferably, the suspending agent is selected from sodium carboxymethylcellulose or xanthan gum.

In the process of the present invention, preferably, the flocculating agent is selected from citrate or tartrate.

In the method of the present invention, preferably, the wetting agent is selected from poloxamer 188.

In the process according to the invention, preferably, the filler is selected from sucrose, lactose, mannitol or maltitol.

Preferably, in step (1), the concentration of acrylic resin IV in the oil phase is 0.1-0.2g/mL. Specifically, it may be 0.1g/mL, 0.11g/mL, 0.12g/mL, 0.13g/mL, 0.14g/mL, 0.15g/mL, 0.16g/mL, 0.17g/mL, 0.18g/mL, 0.19g/mL or 0.2g/mL.

Preferably, in step (2), the emulsifier in the aqueous phase is present in a concentration of 0.05 to 1% by weight. Specifically, it may be 0.05 wt%, 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, or 1 wt%.

In the method of the present invention, there is no particular requirement for the selection of the organic solvent, and it may be an organic solvent immiscible with water, which is conventionally used in the art. Preferably, the organic solvent is selected from dichloromethane and/or ethyl acetate.

In the method of the present invention, there is no particular requirement for the selection of the emulsifier, and various emulsifiers conventionally used in the art may be used. Preferably, the emulsifier is selected from polyvinyl alcohol, poloxamer 188 or polysorbate 80.

In a preferred embodiment, in step (3), the oil phase and the aqueous phase are used in a volume ratio of 1:5-15. Specifically, the ratio of 1:5, 1:6, 1:7, 1:8, 1:9, 1, 10, 1, 11, 1.

In the method of the present invention, in order to reduce the volatilization of the organic solvent and avoid the high temperature during the emulsification process, the surface of the microspheres is solidified, resulting in the breakage of the microspheres, in step (3), the temperature of the aqueous phase may be reduced to 5 to 15 ℃ in advance, and then the oil phase is added dropwise under stirring.

In the method of the present invention, in the step (3), the stirring speed when the oil phase is dropped into the water phase is preferably 2000 to 6000r/min.

In a specific embodiment, in step (3), the stirring speed when the oil phase is dropped into the water phase may be 800r/min, 1000r/min, 1500r/min, 2000r/min, 2500r/min, 3000r/min, 3500r/min, 4000r/min, 4500r/min, 5000r/min, 5500r/min, 6000r/min, 6500r/min, 7000r/min, 7500r/min, or 8000r/min.

In the method of the present invention, in step (3), the oil phase may be added dropwise to the aqueous phase using a peristaltic pump or a dropping funnel, which is a means commonly used in the art.

In a preferred embodiment, in step (3), the stirring speed is 800 to 8000r/min and the stirring time is 1 to 5min while the stirring is continued.

Further preferably, in the step (3), the stirring speed at the time of continuing the stirring is kept in agreement with the stirring speed at the time of dropping the oil phase.

In the method of the present invention, in the step (4), the water-washed product is mixed with the mannitol aqueous solution, which helps to improve the redispersibility of the microspheres when the dry suspension is suspended with water.

In a preferred embodiment, in step (3), the oil phase and the aqueous phase are used in a volume ratio of 1.

Further preferably, in the step (4), the concentration of mannitol in the mannitol aqueous solution is 0.5 to 3% by weight. Specifically, it may be 0.5 wt%, 1 wt%, 1.5 wt%, 2 wt%, 2.5 wt%, or 3 wt%.

In the method of the present invention, in the step (4), there is no particular requirement for the conditions of freeze-drying, and it is sufficient to achieve effective removal of water.

The present invention will be described in detail below by way of examples, but the scope of the present invention is not limited thereto.

The reagents used in the following examples and comparative examples are all commercially available products unless otherwise specified.

Example 1

S1: preparation of spironolactone microspheres:

(1) Mixing spironolactone, acrylic resin IV and an organic solvent (dichloromethane) to obtain an oil phase; wherein the concentration of the acrylic resin IV in the oil phase is 0.14g/mL, and the weight ratio of the spironolactone to the acrylic resin IV is 1:9;

(2) Mixing an emulsifier (polyvinyl alcohol) and water to obtain a water phase, wherein the concentration of the polyvinyl alcohol in the water phase is 0.2 wt%;

(3) Cooling the water phase to 10 ℃, dropwise adding the oil phase obtained in the step (1) into the water phase obtained in the step (2) under stirring at a stirring speed of 3000r/min, and continuously stirring at a speed of 3000r/min for 2min after dropwise adding is finished to obtain an O/W emulsion; wherein the volume ratio of the dosage of the oil phase to the dosage of the water phase is 1;

(4) Removing the organic solvent in the O/W emulsion by rotary evaporation at 40 ℃, then washing for 3 times, then mixing the washing product with a mannitol aqueous solution (the concentration of the mannitol is 1 weight percent), and then carrying out freeze drying to obtain spironolactone microspheres;

s2: preparing a dry suspension:

respectively pulverizing suspending agent (xanthan gum), flocculant (sodium citrate), wetting agent (poloxamer 188) and filler (sucrose), sieving with 60 mesh sieve, and collecting undersize;

sieving the spironolactone microspheres with a 60-mesh sieve, and taking undersize;

mixing the screened spironolactone microspheres, the suspending agent, the flocculating agent, the wetting agent and the filling agent to obtain a dry suspension; the dry suspension comprises 72 wt% of spironolactone microspheres, 4 wt% of a suspending agent, 6 wt% of a flocculating agent, 10 wt% of a wetting agent and 8 wt% of a filling agent, wherein the total weight of the dry suspension is 100 wt%.

Example 2

The procedure was followed as described in example 1, except that in step (1), spironolactone and acrylic resin No. IV were used in a weight ratio of 3.

Example 3

The procedure was as described in example 1, except that in step (1), spironolactone and acrylic resin No. IV were used in a weight ratio of 1:4.

Example 4

The procedure was as described in example 1, except that in step (1), spironolactone and acrylic resin No. IV were used in a weight ratio of 1:3.

Example 5

The procedure was as described in example 1, except that spironolactone and acrylic resin No. IV were used in a weight ratio of 3:7 in step (1).

Test example 1

1. Characterization of Spirolactone microspheres prepared in examples 1-5

(1) Particle size and particle size distribution of spironolactone microspheres:

about 0.3g of spironolactone microspheres are weighed and dispersed in 30mL of 0.1% polysorbate 80 solution, dispersed for 2min with 200W of ultrasound, and detected by a Mastersizer 3000 Malvern laser diffraction method particle size analyzer.

The determination method comprises the following steps: rotation speed 3000rpm, dispersant: water, shading rate 10%.

(2) Determination of drug loading and encapsulation efficiency of spironolactone microspheres

The content of the drug in the spironolactone taste-masking microspheres is measured by High Performance Liquid Chromatography (HPLC). The chromatographic conditions were as follows:

a chromatographic column: ZORBAX SB-C18 column (4.6X 150mm,5 μm); mobile phase: acetonitrile-water solution (1, v/v); flow rate: 1.0mL/min; detection wavelength: 238nm; column temperature the method comprises the following steps: 30 ℃; sample introduction amount: 20 μ L.

The solution preparation method comprises the following steps:

control solution: weighing 0.075g of spironolactone as a reference substance in a 100mL volumetric flask, adding a proper amount of acetonitrile-water solution (1,v/v), carrying out ultrasonic treatment for 5min until the spironolactone is completely dissolved, diluting the spironolactone-water solution (1,v/v) to a scale, and shaking up; precisely measuring 5mL into a 50mL measuring flask, diluting the acetonitrile-water solution (1,v/v)) to a scale, and shaking up; thus obtaining the spironolactone reference substance solution with 75 mu g/mL.

Test solution: accurately weighing 0.05g of spironolactone microspheres in a 10mL measuring flask, adding a proper amount of acetonitrile, carrying out ultrasonic treatment for 20min until the spironolactone microspheres are completely dissolved, diluting the acetonitrile to a scale, shaking up, and centrifuging at 8000rpm for 10min; precisely measuring 1mL of the supernatant into a 10mL measuring flask, diluting the acetonitrile-water solution (1, v/v) to scale, shaking uniformly, centrifuging at 12000rpm for 10min, and taking the supernatant to obtain a test solution.

Drug loading = microsphere traditional Chinese medicine substance/microsphere weighing amount × 100%

Encapsulation efficiency = actual microsphere drug-loading/theoretical microsphere drug-loading × 100%

The results are shown in Table 1.

TABLE 1

Note: d ₁₀ Corresponding to a particle size distribution number of 10%And (4) the particle size. D ₅₀ The particle size is the particle size corresponding to the particle size distribution number of 50%. D ₉₀ The particle size is 90% of the particle size distribution. D ₁₀₀ The particle size is represented by the number of particle size distributions of 100%.

The results show that the spironolactone microspheres prepared in examples 1-5 all had particle sizes less than 80 μm, D ₁₀₀ Less than 80 μm, and the encapsulation efficiency is over 90%. The spironolactone microspheres prepared in examples 1 to 5 have a small particle size and a high encapsulation efficiency, and when the spironolactone microspheres are prepared into a dry suspension and dispersed in water, the dry suspension does not have a gritty feeling when being taken orally, and the dispersion uniformity of the drug is improved.

2. Determination of sedimentation volume ratio and redispersibility of spironolactone taste-masking dry suspensions for children prepared in examples 1 to 5

(1) And (3) determining the sedimentation volume ratio: an appropriate amount of spironolactone taste-masking dry suspension formulation for children (about 250mg equivalent to spironolactone) was weighed into a beaker, 50mL of drinking water was added, and dispersed uniformly. Transferred to a stoppered graduated cylinder. The initial height H0 of the suspension was recorded, left to stand for 3H, the height H of the suspension was again recorded and the sedimentation volume ratio (F) of the suspension was calculated. The value of F should be between 0 and 1, with a larger value representing a more stable suspension.

Sedimentation volume ratio (F) = H/H0

(2) Measurement of redispersibility: an appropriate amount of the spironolactone taste-masking dry suspension for children (about 250mg of spironolactone) is weighed into a beaker, 50mL of drinking water is added, and the mixture is uniformly dispersed. The mixture was transferred to a stoppered cylinder and the stoppered plug was allowed to stand for 3 days. And (5) repeatedly shaking the suspension after standing by a plug measuring cylinder to uniformly disperse, and recording the shaking times. The cylinder with the plug was inverted once and the dwell 5s was recorded as shaking once. The smaller the number of shaking, the better the redispersibility.

The results are shown in Table 2.

TABLE 2

	Example 1	Example 2	Example 3	Example 4	Example 5
						Volume ratio of sedimentation	0.85	0.84	0.89	0.78	0.72
Redispersibility	2	2	2	2	3

As can be seen from table 2, the dry suspensions prepared in examples 1 to 5 have excellent stability and redispersibility.

Example 6

S1: preparation of spironolactone microspheres:

(1) Mixing spironolactone, acrylic resin IV and an organic solvent (dichloromethane) to obtain an oil phase; wherein the concentration of the acrylic resin IV in the oil phase is 0.1g/mL, and the weight ratio of the spironolactone to the acrylic resin IV is 2:8;

(4) Removing the organic solvent in the O/W emulsion by rotary evaporation at 40 ℃, then washing for 3 times, then mixing the washing product with a mannitol aqueous solution (the concentration of mannitol is 1 weight percent), and then carrying out freeze drying to obtain spironolactone microspheres;

s2: preparing a dry suspension:

Example 7

The procedure was as described in example 6, except that in the step (1), the concentration of the acrylic resin IV in the oil phase was 0.2g/mL.

Example 8

The procedure was as in example 6, except that in step (1), the concentration of acrylic resin IV in the oil phase was 0.14g/mL; in the step (3), the volume ratio of the dosage of the oil phase to the dosage of the water phase is 1:5.

Example 9

The procedure was as in example 6, except that in step (1), the concentration of acrylic resin IV in the oil phase was 0.14g/mL; in the step (3), the volume ratio of the dosage of the oil phase to the dosage of the water phase is 1.

Example 10

The procedure was as described in example 6, except that in step (1), the concentration of the acrylic resin IV in the oil phase was 0.14g/mL; in the step (3), the oil phase obtained in the step (1) is dripped into the water phase obtained in the step (2) under the stirring of the stirring speed of 800 r/min.

Example 11

The procedure was as described in example 6, except that in step (1), the concentration of the acrylic resin IV in the oil phase was 0.14g/mL. In the step (3), the oil phase obtained in the step (1) is dripped into the water phase obtained in the step (2) under the stirring condition that the stirring speed is 8000r/min.

Test example 2

Spirolactone microspheres prepared in examples 6-11 were characterized in the same manner as in test example 1, and the results are shown in Table 3.

TABLE 3

Note: d ₁₀ The particle size is represented by the number of particle size distributions of 10%. D ₅₀ The particle size is the particle size corresponding to the particle size distribution number of 50%. D ₉₀ The particle size is 90% of the particle size distribution. D ₁₀₀ The particle size is represented by the number of particle size distributions of 100%.

The results show that the spironolactone microspheres prepared in examples 6 to 11 have smaller particle sizes and higher encapsulation efficiencies. Wherein the stirring speed in the step (3) in the preparation process has great influence on the particle size and the encapsulation efficiency of the spironolactone microspheres, for example, when the stirring speed is 800r/min, the particle size is remarkably increased, but D ₁₀₀ Still less than 150 μm, and the encapsulation efficiency is higher due to larger particle size; when the stirring speed is 3000r/min, the particle size is remarkably reduced, D ₁₀₀ Less than 80 μm and encapsulation efficiency greater than 95%; when the stirring speed is increased to 8000r/minIn this case, the particle diameter is further decreased, D ₁₀₀ Less than 20 μm, the encapsulation efficiency is also low, but still more than 85%, due to the small particle size, and furthermore, it takes a long time to collect microspheres due to the small particle size.

2. The sedimentation volume ratio and redispersibility of the spironolactone taste-masking dry suspensions for children prepared in examples 6 to 11 were measured in the same manner as in test example 1, and the results are shown in Table 4.

TABLE 4

	Example 6	Example 7	Example 8	Example 9	Example 10	Example 11
							Volume ratio of sedimentation	0.90	0.81	0.89	0.92	0.5	0.94
Redispersibility	2	2	2	2	3	4

As can be seen from table 4, the spironolactone taste-masking dry suspensions for children prepared in examples 6 to 9 had excellent stability and redispersibility, wherein the sedimentation ratio of the spironolactone taste-masking dry suspension for children prepared in example 10 was slightly lower than 0.5 but still satisfied the administration requirement, and the spironolactone taste-masking dry suspension for children prepared in example 11 had slightly inferior redispersibility but still satisfied the administration requirement.

Example 12

S1: preparation of spironolactone microspheres:

(1) Mixing spironolactone, acrylic resin IV and an organic solvent (dichloromethane) to obtain an oil phase; wherein the concentration of the acrylic resin IV in the oil phase is 0.14g/mL, and the weight ratio of the spironolactone to the acrylic resin IV is 2:8;

s2: preparing a dry suspension:

mixing the screened spironolactone microspheres, a suspending agent, a flocculating agent, a wetting agent and a filling agent to obtain a dry suspension; the dry suspension comprises 72 wt% of spironolactone microspheres, 3 wt% of a suspending agent, 5 wt% of a flocculating agent, 12 wt% of a wetting agent and 8 wt% of a filling agent, wherein the total weight of the dry suspension is 100 wt%.

Example 13

The method of example 12 is used, except that in step S2, the dry suspension comprises 72 wt% of spironolactone microspheres, 4 wt% of suspending agent, 6 wt% of flocculating agent, 10 wt% of wetting agent, and 8 wt% of filler, based on the total weight of the dry suspension taken as 100 wt%.

Example 14

Except that the method of example 12 was used, step S2 was performed using a dry suspension comprising 72 wt% spironolactone microspheres, 5 wt% suspending agent, 7 wt% flocculating agent, 8 wt% wetting agent, and 8 wt% filler, based on the total weight of the dry suspension taken as 100 wt%.

Example 15

The process of example 12 was followed, except that in step S2, the suspending agent used was sodium carboxymethylcellulose.

Example 16

The method of example 12 was used, except that in step S2, the suspending agent used was sodium carboxymethylcellulose and the dry suspension comprised 72 wt% spironolactone microspheres, 4 wt% suspending agent, 6 wt% flocculating agent, 10 wt% wetting agent and 8 wt% filler, based on the total weight of the dry suspension taken as 100 wt%.

Example 17

The method of example 12 was used, except that in step S2, the suspending agent used was sodium carboxymethylcellulose, and the dry suspension contained 72 wt% spironolactone microspheres, 5 wt% suspending agent, 7 wt% flocculating agent, 8 wt% wetting agent, and 8 wt% filler, based on 100 wt% total weight of the dry suspension.

Comparative example 1

Respectively crushing spironolactone, xanthan gum, sodium citrate, poloxamer 188 and sucrose, sieving by a 60-mesh sieve, removing undersize, and then mixing the spironolactone, the xanthan gum, the sodium citrate, the poloxamer 188 and the sucrose after sieving to obtain a spironolactone dry suspension; wherein the total weight of the spironolactone dry suspension is 100 percent by weight, and the spironolactone dry suspension contains 14.4 percent by weight of spironolactone (D) ₉₀ ＝23.2μm，D ₁₀₀ =38.7 μm), 4 wt.% xanthan gum, 6 wt.% sodium citrate, 10 wt.% poloxamer 188, 8 wt.% sucrose and 57.6 wt.% mannitol.

Comparative example 2

Commercially available spironolactone sheet grinding powder

According to the clinical application method of spironolactone, a proper amount of commercially available spironolactone tablets are taken, ground into fine powder and sieved by a 60-mesh sieve for later use. The mass percent of spironolactone in the commercially available spironolactone tablets is 25%.

Wherein the specification of commercially available spironolactone tablets is 20mg (manufacturer: commercially available spironolactone tablets)

Comparative example 3

The procedure was as described in example 12, except that in step (1), spironolactone and acrylic resin No. IV were used in a weight ratio of 1:1.

Test example 3

The spironolactone taste-masking dry suspensions for children prepared in examples 12 to 17 and comparative examples 1 to 3 were measured for sedimentation volume ratio and redispersibility in the same manner as in test example 1, and the results are shown in Table 5.

TABLE 5

As can be seen from Table 5, the spironolactones for children prepared in examples 12-17The dry suspension has a sedimentation volume ratio of more than 0.75, good redispersibility, and 2 or 3 shaking times. In contrast, in comparative example 1, the particle size of the raw material drug is small, the sedimentation volume ratio is similar to that of the spironolactone taste-masking dry suspension for children prepared in the examples, but the raw material drug particles are irregular in shape, so that the redispersibility after sedimentation is poor, and the raw material drug particles can be uniformly dispersed only by shaking 10 times. Comparative example 2 in reference to the clinical use method, commercially available spironolactone tablets were ground into fine powder, and the drug was almost completely settled without suspending agent, wetting agent and flocculating agent, the sedimentation volume ratio was 0.05, and the redispersibility was poor, and the uniform dispersion was not achieved even when shaken 20 times. The weight ratio of the spironolactone to the acrylic resin IV contained in the comparative example 3 is 1:1, and due to the higher weight ratio of the medicaments, the phenomena of emulsion breaking and microsphere adhesion (D) occur in the preparation process of the microspheres ₁₀ ＝51.5μm，D ₅₀ ＝92.1μm，D ₉₀ ＝156.3μm，D ₁₀₀ =211.2 μm), sedimentation was faster and redispersibility was slightly poor.

Test example 4

The post-suspension sub-dose accuracy of the spironolactone taste-masking dry suspensions for children prepared in examples 1-5 and 10-17, the dry suspensions prepared in comparative examples 1 and 3, and the commercially available spironolactone milled powder of comparative example 2 were determined.

High Performance Liquid Chromatography (HPLC) was used to determine the accuracy of the sub-doses after suspension. The chromatographic conditions were as follows:

a chromatographic column: ZORBAX SB-C18 column (4.6X 150mm,5 μm); mobile phase: acetonitrile-water solution (1, v/v); flow rate: 1.0mL/min; detection wavelength: 238nm; column temperature: 30 ℃; sample injection amount: 20 μ L.

The solution preparation method comprises the following steps:

Test solution: appropriate amounts of the spironolactone taste-masking dry suspensions for children prepared according to examples 1 to 5 and examples 10 to 17, the spironolactone dry suspensions of comparative example 1 and comparative example 3, and the commercially available spironolactone tablet mill flour of comparative example 2 (approximately equivalent to 250mg of spironolactone) were weighed into a beaker, 50mL of drinking water was added, dispersed uniformly, and transferred to a 50mL measuring cylinder. Precisely transferring 1mL of suspension into a 50mL measuring flask respectively at different positions (10 positions, 1 sampling point at each position), adding an appropriate amount of acetonitrile, performing ultrasonic treatment until spironolactone is completely dissolved, cooling to room temperature, diluting to a scale with acetonitrile-water (1, v/v), shaking uniformly, and centrifuging at 10000rpm for 10min; 5mL of the supernatant was removed by pipetting into a 50mL volumetric flask, diluted to the mark with acetonitrile-water (1,v/v), shaken well, filtered through a 0.45 μm filter and the filtrate was sampled. 10 dots were taken for each suspension.

The spirolactone content in each test sample is calculated, and the deviation (RSD%) of the relative standard sample is calculated, so that the smaller the RSD value is, the more uniform the dispersion of the medicine in the suspension is, and the more accurate the divided dose is. The results are shown in Table 6.

TABLE 6

As can be seen from Table 6, the RSD of the spironolactone taste-masking dry suspensions for children prepared in examples 1-5 and examples 10-17 is less than 2%, and the accuracy of the divided dose can be ensured.

The RSD of the comparative example 1 is more than 5 percent, and the particles of the bulk drug have irregular shapes, so the particles have poor dispersibility in suspension and cannot be uniformly dispersed; the RSD of comparative example 2 was as high as 15.78% because comparative example 2 did not contain suspending agent, wetting agent and flocculating agent, and the abrasive particles were large and difficult to disperse uniformly, and during sampling, the drug particles settled rapidly, resulting in a mean drug concentration of less than 5mg/mL and a large RSD value; the RSD of the comparative example 3 is more than 5%, and the spironolactone microspheres are high in drug weight ratio, so that the microspheres are adhered, quickly settle in suspension and cannot be uniformly dispersed. Therefore, the accuracy of the divided dose cannot be ensured in comparative example 1, comparative example 2, and comparative example 3.

Test example 5

Evaluation of Release in Drinking Water of Spirolactone taste-masking Dry suspensions for Children prepared in examples 1-5 and examples 10-17, dry suspensions prepared in comparative example 1 and comparative example 3, and commercial Spirolactone Mill powder of comparative example 2

Appropriate amounts (about 250mg equivalent to spironolactone) of the dry suspension and commercially available spironolactone tablet grinding powder were weighed, respectively, added to 1000mL of drinking water, and stirred at room temperature for 30min at a rotation speed of 50rpm. Sampling at 10min, 20min and 30min, determining the concentration of the medicinal materials in the drinking water by high performance liquid chromatography, and calculating the release rate. The results are shown in Table 7.

TABLE 7

As can be seen from Table 7, the dissolution speed of the spironolactone dry suspension prepared in the comparative example 1 and the commercially available spironolactone tablet grinding powder in the comparative example 2 in drinking water is high, and the dissolution rate of the medicine can reach more than 5% within 10min, so that the medicine can be released in the oral cavity to generate bitter taste in the medicine taking process. In comparative example 3, the weight ratio of the medicine in the spironolactone microspheres is high, the medicine cannot be completely embedded in the microsphere structure, the dissolution speed in drinking water is high, the dissolution rate of the medicine reaches more than 2% in 10min, the dissolution rate of the medicine reaches more than 6% in 30min, and the medicine can be released in the oral cavity to generate bitter taste in the process of taking the medicine and cannot be taken later.

The spironolactone taste-masking dry suspension for children prepared by the invention can obviously reduce the release rate of the drug in drinking water, and the drug release rate is not enough to be 0.5% in 30 min. The results show that the spironolactone taste-masking dry suspension for children prepared by the method can improve the bitter taste caused by drug dissolution during taking, achieve the taste-masking effect, ensure that the suspension can be taken after a long time, and improve the drug compliance of children.

Test example 6

Dissolution evaluation in simulated gastric fluid of the sprinolide taste-masking dry suspensions for children prepared in examples 1-5 and examples 10-17, the dry suspensions prepared in comparative example 1 and comparative example 3, and the commercially available sprinolide milling powder of comparative example 2

And respectively weighing a proper amount (equivalent to 20mg of spironolactone)) of the dry suspension and commercially available spironolactone tablet grinding powder, placing the dry suspension and the commercially available spironolactone tablet grinding powder into a dissolution instrument, and determining the dissolution rate by adopting a slurry method. Dissolution medium: aqueous hydrochloric acid at pH = 1.2; the volume of the dissolution medium is: 1000mL; rotating speed: 100rpm; temperature: 37 +/-0.5 ℃. 5mL samples are taken at 5min, 10min, 20min, 30min, 60min and 120min respectively, and simultaneously, equal volumes of dissolution medium at the same temperature are added. The drug concentration in the dissolution medium is measured by high performance liquid chromatography, and the dissolution rate is calculated.

The results are shown in Table 8.

TABLE 8

Time

5min

10min

20min

30min

60min

120min

Example 1

68.9％

89.7％

92.3％

94.5％

96.7％

98.7％

Example 2

67.4％

87.5％

93.2％

93.6％

94.7％

95.6％

Example 3

66.5％

88.9％

90.1％

94.2％

95.6％

96.8％

Example 4

61.4％

85.2％

91.2％

92.3％

93.4％

94.2％

Example 5

56.3％

81.3％

87.2％

89.3％

90.4％

92.8％

Example 10

61.2％

82.3％

88.1％

90.1％

91.2％

93.4％

Example 11

68.9％

89.4％

93.2％

94.6％

95.6％

97.1％

Example 12

65.4％

87.3％

89.7％

93.4％

94.7％

95.8％

Example 13

68.9％

89.1％

90.4％

95.6％

96.8％

98.9％

Example 14

64.6％

88.5％

91.2％

93.5％

94.6％

94.9％

Example 15

64.8％

88.3％

91.2％

95.6％

96.7％

97.8％

Example 16

66.3％

89.9％

91.1％

92.3％

93.7％

95.0％

Example 17

65.1％

87.3％

90.4％

94.8％

96.7％

99.3％

Comparative example 1

23.3％

45.6％

61.3％

73.4％

85.1％

89.6％

Comparative example 2

21.4％

44.3％

59.1％

75.6％

83.1％

87.5％

Comparative example 3

39.4％

59.7％

71.2％

79.7％

86.7％

88.2％

As can be seen from Table 8, since spironolactone is a poorly soluble drug, the dissolution rate of the spironolactone dry suspension prepared in comparative example 1 and the dissolution rate of the commercially available spironolactone tablet grinding powder in comparative example 2 in simulated gastric fluid are slow, and the drug dissolution rate is less than 50% at 10min and less than 90% at 120 min. In comparative example 3, the weight ratio of the medicine in the spironolactone microspheres is high, the dissolution promoting effect of the acrylic resin IV on the medicine is weak, and the dissolution speed is remarkably lower than that of examples 1-5 and examples 10-17, wherein the dissolution rate of the medicine is less than 60% in 10min and less than 90% in 120 min.

The spironolactone taste-masking dry suspension for children prepared by the invention has the advantages that the adopted acrylic resin IV is dissolved in acid, the spironolactone in the microspheres can be promoted to be rapidly dissolved into simulated gastric juice, the dissolution speed is high, and the spironolactone can reach more than 80% in 10 min. The results show that the spironolactone taste-masking dry suspension for children prepared by the method can obviously reduce the dissolution rate of spironolactone in drinking water and can also obviously improve the dissolution rate and dissolution rate of the medicine in simulated gastric juice environment.

Test example 7

Taste masking effect evaluation of Spirolactone taste-masking Dry suspensions for Children prepared in examples 1-5 and examples 10-17, dry suspensions prepared in comparative example 1 and comparative example 3, and commercial Spirolactone Mill powder of comparative example 2

Appropriate amount (equivalent to 250mg of spironolactone)) of the dry suspension and commercially available spironolactone sheet grinding powder are respectively weighed and placed in a beaker, 50mL of drinking water is respectively added, and the mixture is uniformly dispersed to prepare suspension. The taste was tasted by 10 healthy adult volunteers. The volunteers took the different suspensions in the mouth for 5 seconds and then spit out, and evaluated the different suspensions for bitterness and grittiness.

The bitterness evaluation score was set to 0-5, and the scoring criteria: 0 point, no bitter taste; 1 minute, slightly bitter after being taken for 5 seconds; 2 minutes, after being taken for 5 seconds, the tea has bitter taste; 3 minutes, after being taken orally for 5 seconds, the tea has obvious bitter taste; 4 minutes, the bitter taste exists after the medicine is taken for 1 second; 5 minutes, 1 second of buccal administration shows obvious bitter taste.

The evaluation score of the sand feeling is set to be 0-5, and the scoring standard is as follows: 0 minute, no gritty feel; 1 minute, no obvious sand feeling; 2 points, slight sand feeling; 3 points, sand feel; 4 points, sand feeling is obvious; 5 points, very strong gritty feeling.

The results are shown in Table 9.

Scoring	Bitter taste	Feeling of sand
			Example 1	0	0
Example 2	0	0
			Example 3	0	0
Example 4	0	0
			Example 5	1	0
Example 10	0	1
			Example 11	1	0
Example 12	0	0
			Example 13	0	0
Example 14	0	0
			Example 15	0	0
Example 16	0	0
			Example 17	0	0
Comparative example 1	5	1
			Comparative example 2	5	5
Comparative example 3	5	4

As can be seen from table 9, the spironolactone dry suspension prepared in comparative example 1 and the commercially available spironolactone tablet mill flour of comparative example 2 both had a significant bitter taste due to the direct dispersion of the drug in water and the dissolution of a portion of the drug in water; the comparative example 2 is the grinding powder, so that the particles are large and have extremely strong sand feeling. In the spironolactone dry suspension prepared in the comparative example 3, the polyacrylate IV has poor drug embedding effect, and part of the drug is dissolved in water and has obvious bitter taste; due to the larger size of the microspheroidal particles, D ₁₀₀ At 211.2 μm, a marked gritty feel was present.

The spironolactone taste-masking dry suspension for children prepared by the invention has very low bitter taste and sand grain taste scores due to extremely low dissolution rate of the medicine in water. The results show that the spironolactone taste-masking dry suspension for children prepared by the method can effectively prevent the drug from dissolving in drinking water in the drug taking process, the drug release degree is less than 0.5 percent after the spironolactone taste-masking dry suspension is placed in the drinking water for 30min, the bitter taste of the drug can be effectively masked, and the drug compliance is improved.

Based on the results of test examples 1 to 7, it can be seen that the particle size D of the spironolactone microsphere for children prepared by the preparation method provided by the present invention ₁₀₀ Less than 150 mu m, the prepared spironolactone taste-masking dry suspension for children has no obvious gritty feeling when being suspended in water for taking, and can further ensure the medication compliance of children patients. And the medicine is dispersed more uniformly in water, so that the accuracy of the divided dose can be ensured.

The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the scope of the invention.

Claims

1. A spironolactone taste-masking dry suspension for children is characterized by comprising spironolactone microspheres, a suspending agent, a flocculating agent, a wetting agent and a filling agent;

the spironolactone microspheres contain spironolactone and acrylic resin IV; the particle diameter D of the spironolactone microspheres ₁₀₀ Less than 150 μm;

2. A spironolactone taste-masking dry suspension for children according to claim 1, wherein the dry suspension comprises 69-75 wt.% spironolactone microspheres, 3-5 wt.% suspending agent, 5-7 wt.% flocculating agent, 8-12 wt.% wetting agent and 1-10 wt.% filler, based on 100 wt.% of the total weight of the dry suspension.

3. A preparation method of spironolactone taste-masking dry suspension for children is characterized by comprising the following steps:

s1: preparation of spironolactone microspheres:

(2) Mixing an emulsifier and water to obtain a water phase;

s2: preparing a dry suspension:

4. The method of claim 3, wherein in step S2, the dry suspension comprises 69-75 wt% of spironolactone microspheres, 3-5 wt% of a suspending agent, 5-7 wt% of a flocculating agent, 8-12 wt% of a wetting agent, and 1-10 wt% of a filler, based on the total weight of the dry suspension taken as 100 wt%.

5. The method according to claim 3 or 4, wherein the mesh size of the screen used for the screening in step S2 is 40 to 100 mesh.

6. The method according to claim 3, wherein in step (1), the concentration of acrylic resin IV number in the oil phase is 0.1-0.2g/mL.

7. The process according to claim 3, wherein in step (2), the emulsifier in the aqueous phase is present in a concentration of 0.05 to 1% by weight.

8. The process according to claim 3 or 4, characterized in that the organic solvent is selected from dichloromethane and/or ethyl acetate;

9. The process of claim 3, wherein in step (3), the oil phase and the aqueous phase are used in a volume ratio of 1:5-15.

10. The method according to claim 3 or 4, wherein in step (4), the concentration of mannitol in the aqueous mannitol solution is 0.5 to 3% by weight.