Medicinal pregelatinized starch as well as preparation method and application thereof

Abstract

The invention discloses medicinal pregelatinized starch as well as a preparation method and application thereof, and the preparation method of the medicinal pregelatinized starch comprises the following steps: adding starch into a salt solution with the mass fraction of 0.1-0.8%, and stirring at the temperature of 75-95 DEG C to form uniform starch slurry; putting the obtained starch slurry into a grinding device, adding polyhydric alcohol, and grinding for 30-50 minutes; putting the obtained product into an extruder, controlling the temperature of a screw rod, and extruding at a certain temperature; and cooling and drying the extruded product, and cutting and crushing the extruded product by using a granulator to obtain the pregelatinized starch. The invention provides a novel preparation method of pregelatinized starch, which comprises the following steps: dissolving starch by using a salt solution, mixing, grinding and activating by using polyhydric alcohols, and selecting different salt solutions and types of polyhydric alcohols, so that the viscosity of the prepared pregelatinized starch is controllable, and meanwhile, a preparation method of the pregelatinized starch with lower viscosity is provided; a new thought is provided for the preparation of the pregelatinized starch.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and particularly relates to a pharmaceutical pregelatinized starch, a preparation method thereof, and an application thereof. Background Art

[0002] Pregelatinized starch is a common pharmaceutical excipient, commonly used as a binder, disintegrant, and diluent. In the prior art, through the previous high-temperature and high-pressure mechanical activation treatment, the obtained pregelatinized starch has better fluidity and compressibility than traditional starch, and is used as a binder for direct compression of whole powder. Compared with other types of binders, pregelatinized starch has the characteristics of wide source and low cost. However, the pregelatinized starch produced by the existing process often has problems such as poor fluidity and uneven viscosity. The performance of pregelatinized starch directly affects the disintegration and dissolution performance of oral solid preparations, and further affects the quality and therapeutic effect of drugs.

[0003] In order to improve the performance of pregelatinized starch, various solutions have been proposed in the prior art: in one disclosed solution, starch, chlorosulfonic acid, and water are mixed, then mixed and stirred with salicylic acid, sodium alginate, and xylitol, and then sodium hypochlorite and alkyl glycoside are added and heated and stirred and then extruded. In another disclosed solution, starch is dissolved in citric acid, then ball-milled with absolute ethanol, and the extruded material is cooled and dried and then cut and pulverized to obtain a pregelatinized starch. The pregelatinized starch prepared by this method has a loose structure, uniform particles, low viscosity, good fluidity, fast dissolution rate, and high solubility. In this technology, acidic reagents are used to promote starch activation, thus achieving a better pregelatinization effect. However, the performance parameters of the product, including viscosity, cannot be adjusted by changing the technical solution, and the scope of application of the product cannot be expanded. Summary of the Invention

[0004] In view of the deficiencies of the prior art, the present invention provides a pharmaceutical pregelatinized starch, a preparation method thereof, and an application thereof, which can achieve controllable product viscosity.

[0005] As the first aspect of the present invention, it lies in providing a preparation method of a pharmaceutical pregelatinized starch, comprising the following steps: Step 1, preparation of starch slurry: Add starch to a salt solution with a mass fraction of 0.1% - 0.8%, and heat and stir to form a uniform starch slurry; Step 2, grinding and activation: Place the starch slurry obtained in Step 1 in a grinding device, add polyol, and grind for 30 - 50 min; Step 3, heating and extrusion: Place the product obtained in Step 2 in an extruder, control the screw temperature, and heat and extrude; Step 4, post-treatment: Cool and dry the extruded product obtained in Step 3, and cut and pulverize it with a granulator to obtain pregelatinized starch. The drying methods include freeze drying, microwave heating drying, steam drying, etc.

[0006] In one or more embodiments of the present invention, in step 1, the salt solution includes an aqueous solution of at least one of sodium chloride, potassium chloride, calcium chloride, sodium acetate, and sodium citrate, and is preferably an aqueous solution of sodium acetate.

[0007] In one or more embodiments of the present invention, in step 1, the starch is selected from corn starch, tapioca starch, potato starch, or wheat starch.

[0008] More preferably, in step 1, the heating and stirring temperature is 75-95°C, preferably 80-90°C.

[0009] More preferably, in step 1, the mass ratio of starch to the salt solution is 1:0.15-0.35.

[0010] In one or more embodiments of the present invention, in step 2, the grinding device is a ball mill.

[0011] In one or more embodiments of the present invention, in step 2, the polyol is an aqueous solution of propylene glycol or glycerol; more preferably, the polyol is a propylene glycol solution with a mass fraction of 8-30% or a glycerol solution with a mass fraction of 3-15%.

[0012] In one or more embodiments of the present invention, through comparison, it is found that using a salt solution can significantly improve the solubility of pregelatinized starch, improve its fluidity, and increase its viscosity. Analyzing the reasons, the activation effect of starch is enhanced by the salt solution treatment method.

[0013] The present invention also uses co-grinding of polyol and starch slurry. By using a polyol with a certain viscosity, the controllable adjustment of the viscosity of the product is achieved by changing the addition of propylene glycol or glycerol.

[0014] Analyzing the effects of different salt types, salt ions weaken the hydrogen bonds between starch molecules, reducing the content of amylopectin; at the same time, they disrupt the electrostatic interaction of hydroxyl groups in starch molecules, enhance the penetration of water molecules, and promote the swelling of starch granules, thereby increasing solubility. Salt ions can promote the close packing of pregelatinized starch granules, thus reducing the compressibility index and improving fluidity; in coordination with polyol, they promote the penetration of water molecules and further increase solubility.

[0015] The research of the present invention also finds that different types of starch result in different viscosities of the prepared pregelatinized starch. Under the same preparation conditions, the viscosity of pregelatinized starch prepared from wheat starch is higher than that from other sources.

[0016] Among different salt types, the acetate ion of sodium acetate may be more likely to combine with water molecules to promote the swelling of starch; at the same time, based on its buffering performance, it can provide a stable pH environment to ensure the stability of product performance.

[0017] Further preferably, in step 2, the mass ratio of the polyol to the starch slurry is 0.15 to 0.3:1.

[0018] In one or more embodiments of the present invention, in step 3, the heating temperature of the extruder is 80 to 100 °C.

[0019] As the second aspect of the present invention, there is provided a pharmaceutical pregelatinized starch prepared by the above preparation method.

[0020] The viscosity of the pregelatinized starch is 2600 to 2900 mPa•s.

[0021] As the third aspect of the present invention, there is provided the use of the pharmaceutical pregelatinized starch prepared by the above preparation method in the preparation of drugs, wherein the drugs are oral preparations, selected from tablets or capsules. The pregelatinized starch provided by the present invention is used as a binder, disintegrant or diluent in the preparation of tablets or capsules.

[0022] Compared with the prior art, the beneficial effects of the present invention are as follows: (1) The present invention provides a new preparation method of pregelatinized starch. First, the starch is dissolved by a salt solution, and then mixed and ground with a polyol for activation. By selecting different salt solutions and types of polyols, the viscosity of the prepared pregelatinized starch can be controlled. At the same time, a preparation method for pregelatinized starch with a higher viscosity is provided, which provides a new idea for the preparation of pregelatinized starch.

[0023] (2) The pregelatinized starch provided by the present invention has good fluidity, fast dissolution rate in cold water and high solubility, which is beneficial to the dissolution of drugs.

[0024] (3) In the preparation method provided by the present invention, when sodium acetate is used to activate starch, due to its buffering effect, it is beneficial to the stability of the pH environment of drugs and improves the product stability. Description of the Drawings

[0025] The specification drawings constituting a part of the present invention are used to provide a further understanding of the present invention. The schematic embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation to the present invention.

[0026] Figure 1 It is the dissolution curve diagram in Example 26. Detailed Embodiments

[0027] It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the technical field to which the present invention belongs.

[0028] Apparatus: Electronic balance: METTLER TOLEDO Instruments Co., Ltd.; Electrothermal constant temperature forced air dryer; Water bath constant temperature oscillator; Rapid viscosity analyzer; Tablet press; Tablet hardness tester, Disintegration time limit tester, Low-speed centrifuge.

[0029] Experimental method: Cold water solubility: Weigh 2.0 g (W) of the pregelatinized starch sample, slowly add it to 100 ml of deionized water that has been kept at a constant temperature, stir continuously, then stir at high speed for 2 minutes, put it into a centrifuge tube, centrifuge at 3000 rpm for 10 minutes, 20 minutes, and 30 minutes. Use a pipette to take out 25 ml of the upper layer solution and dry it to a constant weight at 110 °C to obtain the amount of dissolved starch (A, g). Calculate its solubility (S, %) according to the formula S = A × 4 / W × 100%.

[0030] Compressibility index: Used to characterize the flowability of powders.

[0031] Calculate according to the following formula: 100(V0 - VF) / V0 In the formula, V0 is the apparent volume in the loose state; VF is the tapped volume.

[0032] The embodiments of the present invention provide a preparation method of pregelatinized starch, including the following steps: Step 1, preparation of starch slurry: Add starch to a salt solution with a mass fraction of 0.1% - 0.8%, and form a uniform starch slurry by heating and stirring; In one or more embodiments, the mass fraction of the salt solution can be any value among 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8% or any value between 0.1% - 0.8%.

[0033] In one or more embodiments, the salt is at least one of sodium chloride, sodium acetate, calcium chloride, potassium chloride, or sodium citrate.

[0034] In one or more embodiments, the mass ratio of starch to the salt solution is any value among 1:0.15, 1:0.2, 1:0.25, 1:0.3, 1:0.35 or any value between 1:0.15 - 1:0.35.

[0035] Step 2, grinding and activation: Place the starch slurry obtained in Step 1 in a grinding device, add polyol, and grind for 30 - 50 min; The polyol is at least one of propylene glycol or glycerol.

[0036] In one or more embodiments, the mass ratio of polyol to starch slurry is any value among 0.15:1, 0.2:1, 0.25:1 or 0.3:1, or any value between 0.15:1 and 0.3:1.

[0037] Step 3, heating and extrusion: Place the product obtained in Step 2 in an extruder, control the screw temperature, and perform heating and extrusion. Step 4, post-treatment: Cool and dry the extruded product obtained in Step 3, and cut and pulverize it with a pelletizer to obtain pregelatinized starch.

[0038] Example 1 Take 100 g of wheat starch, add it to 25 g of a sodium chloride solution with a mass fraction of 0.4%, stir evenly at 80 °C to form a starch slurry; transfer the starch slurry to a ball mill, add 20 g of a propylene glycol solution with a content of 15%, and grind for 40 min; transfer the product to an extruder and extrude it at 90 °C; cool the obtained extruded product to 25 °C, freeze-dry it, and cut and pulverize it with a pelletizer to the required particle size range.

[0039] Example 2 Take 100 g of wheat starch, add it to 25 g of a sodium acetate solution with a mass fraction of 0.4%, stir evenly at 80 °C to form a starch slurry; transfer the starch slurry to a ball mill, add 20 g of a propylene glycol solution with a content of 15%, and grind for 40 min; transfer the product to an extruder and extrude it at 90 °C; cool the obtained extruded product to 25 °C, freeze-dry it, and cut and pulverize it with a pelletizer to the required particle size range.

[0040] Example 3 Take 100 g of wheat starch, add it to 25 g of a calcium chloride solution with a mass fraction of 0.4%, stir evenly at 90 °C to form a starch slurry; transfer the starch slurry to a ball mill, add 20 g of a propylene glycol solution with a content of 15%, and grind for 40 min; transfer the product to an extruder and extrude it at 90 °C; cool the obtained extruded product to 25 °C, freeze-dry it, and cut and pulverize it with a pelletizer to the required particle size range.

[0041] Based on the formula and preparation process provided in Example 1, the formulas of the following several examples are provided, and with reference to the standards in the Chinese Pharmacopoeia, the solubility / %, compressibility index / %, and viscosity / mPa•s (15% aqueous solution) are investigated, and the test results are shown in Table 1.

[0042] Table 1, Formulas and Test Results of Each Example

[0043] As can be seen from Table 1, the use of salt solutions can significantly improve the solubility of pregelatinized starch, improve its fluidity, and increase its viscosity. At the same addition amount, sodium acetate and sodium citrate have the most significant activation effect. At the same time, the viscosity of the prepared pregelatinized starch is significantly higher than that of other examples.

[0044] Examples 9 - 14, Influence of Different Salt Solution Concentrations on the Viscosity of the Product In Step 1, sodium acetate with different concentrations was added, and other conditions were carried out according to Example 2. The inspection results of the obtained products are shown in Table 2.

[0045] Table 2, Detection Results of Products Prepared with Different Concentrations of Sodium Acetate

[0046] It can be seen that within the range of 0.1% - 0.8% concentration of sodium acetate, the solubility and fluidity of pregelatinized starch can be improved, and the viscosity can be increased.

[0047] Examples 15 - 21, Influence of Different Polyhydric Alcohols on the Viscosity of the Product In Step 2, alcohols of different types or different concentrations were used, and other conditions were carried out according to Example 2. The inspection results of the obtained products are shown in Table 3.

[0048] Table 3, Detection Results of Products Prepared with Different Polyhydric Alcohols

[0049] It can be seen that adding polyhydric alcohols such as propylene glycol or glycerol will affect the viscosity of pregelatinized starch, while ethanol has a relatively small influence on the viscosity. Analyzing the reason, polyhydric alcohols themselves have a certain viscosity, which affects the treatment effect. Adjusting the addition amount of polyhydric alcohols can control and adjust the viscosity of pregelatinized starch.

[0050] Examples 22 - 24, Influence of Starches from Different Sources on the Viscosity of the Product In Step 1, starches from different sources were used, and other conditions were carried out according to Example 2. The inspection results of the obtained products are shown in Table 4.

[0051] Table 4, Detection Results of Products Prepared with Starches from Different Sources

[0052] It can be seen that the properties of pregelatinized starches prepared from starches of different sources are slightly different. On the premise of the same other conditions, the pregelatinized starch prepared from wheat - sourced starch has a higher viscosity.

[0053] Comparative Example 1 Step 1 is processed as follows: Add sweet potato starch into a 0.08 wt% citric acid aqueous solution with a mass 0.35 times that of the sweet potato starch, and under the condition of 55 °C, perform ultrasonic treatment for 50 min with an ultrasonic frequency of 800000 Hz; other conditions are carried out according to Example 2, and the inspection results of the obtained products are as follows: The solubility is 90.5%, the compressibility index is 18.7, and the viscosity is 905 mPa•s (15% aqueous solution).

[0054] It can be seen that for the improvement of viscosity, the treatment process of the salt solution provided by the present invention has a significant impact.

[0055] Example 25, Performance test of drug tablets Mix the granules prepared in the above examples with 0.3% w / w magnesium stearate and 3% lactose, press tablets, and check the hardness and disintegration time. The results are as follows: Table 5, Performance test results of drug tablets

[0056] From the results, it can be seen that the viscosity of Example 1 is lower than that of Example 2, but the tablets prepared by the latter have the fastest disintegration. Analyzing the reasons, on the one hand, it may be that the content of amylose it contains is higher and the disintegration property is stronger; on the other hand, the pregelatinized starch activated by sodium acetate has a stronger hydration effect, which can better promote the swelling of the pregelatinized starch, thereby improving the solubility and resulting in faster disintegration.

[0057] Example 6 without activation by salt solution has a longer disintegration time.

[0058] Example 26, A drug It contains a drug active ingredient, the medicinal pregelatinized starch prepared in Example 1, and other excipients.

[0059] As a typical example, take 12 parts of candesartan cilexetil, 64 parts of lactose, 13 parts of pregelatinized starch, and 3 parts of hydroxypropyl cellulose; then add 4 parts of polyethylene glycol, 3 parts of carboxymethyl cellulose calcium, and 1 part of magnesium stearate; sieve; dry at 50 - 60 °C, sieve and size the granules, and press tablets. The pregelatinized starch is respectively the products prepared in Example 1, Example 2, Example 3, Example 6, Example 12, and Example 18.

[0060] 1. According to the relevant method for the determination of dissolution in the second part of the Chinese Pharmacopoeia (2010 edition), take 6 tablets of each sample, and use the paddle method to determine the dissolution. The paddle rotation speed is 50 revolutions per minute; the dissolution medium is 900 mL of phosphate buffer solution with a pH of 6.5 + 0.7% Tween 20; sample and detect at 10, 20, 30, 45, and 60 min respectively, and extend the sampling to 90 min for further detection.

[0061] The results are shown in Table 6, and the dissolution curves are as Figure 1 shown.

[0062] Table 6. Cumulative dissolution percentage results of each example

[0063] It can be seen that the pregelatinized starch prepared by different processes significantly affects the dissolution behavior of the drug. The product provided by the present invention improves the disintegration efficiency of the formulation and helps the drug to dissolve fully.

[0064] 2. Stability test (1) Take samples and place them under the conditions of temperature 60°C, 40°C, humidity RH75%, RH92.5% and light intensity 4500Lx ± 500Lx respectively. Sampling is carried out on the 5th day and 10th day respectively, and the dissolution is detected (sampling at 60 min), and compared with day 0.

[0065] According to the relevant method for dissolution determination in the second part of the Chinese Pharmacopoeia 2010 Edition, take 6 tablets of each sample and determine the dissolution by the paddle method. The paddle rotation speed is 50 revolutions per minute; the dissolution medium is 900 mL of HCl solution with pH 2.0 + 0.7% Tween 20.

[0066] The test results are shown in Table 7.

[0067] Table 7. Results of drug stress test

[0068] The stability test under relatively harsh conditions shows that the pregelatinized starch activated by adding salt has good stability. In particular, when using buffer salts, it is more helpful for the stable release of the drug, and it can be fully dissolved even in a lower pH environment.

[0069] The above are only the preferred embodiments of the present invention and are not used to limit the present invention. For those skilled in the art, the present invention can have various changes and modifications. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A method for preparing medicinal pregelatinized starch, characterized in that: The steps include: Step 1, preparation of starch slurry: adding starch to a salt solution with a mass fraction of 0.1% to 0.8%, heating and stirring to form a uniform starch slurry; Step 2, grinding and activation: placing the starch slurry obtained in step 1 in a grinding device, adding polyol, and grinding for 30-50 minutes; Step 3, heating and extrusion: placing the product obtained in step 2 in an extruder, controlling the screw temperature, and heating and extruding; Step 4, post-processing: cooling and drying the extruded product obtained in step 3, and cutting and crushing it with a pelletizer to obtain pregelatinized starch.

2. The method for preparing the medicinal pregelatinized starch according to claim 1, characterized in that: In step 1, the salt solution includes an aqueous solution of at least one of sodium chloride, potassium chloride, calcium chloride, sodium acetate, and sodium citrate, preferably an aqueous solution of sodium acetate or sodium citrate.

3. The method for preparing the medicinal pregelatinized starch according to claim 1, characterized in that: In step 1, the starch is selected from at least one of corn starch, tapioca starch, potato starch or wheat starch.

4. The method for preparing the medicinal pregelatinized starch according to claim 1, characterized in that: In step 1, the heating and stirring temperature is 75-95°C, preferably 80-90°C; in step 3, the extruder heating temperature is 80-100°C.

5. The method for preparing the medicinal pregelatinized starch according to claim 1, characterized in that: In step 1, the mass ratio of starch to salt solution is 1:0.15~0.

35.

6. The method for preparing the medicinal pregelatinized starch according to claim 1, characterized in that: In step 2, the grinding device is a ball mill.

7. The method for preparing the medicinal pregelatinized starch according to claim 1, characterized in that: In step 2, the polyol is an aqueous solution of propylene glycol or glycerol; Preferably, the polyol is a propylene glycol solution with a mass fraction of 8-30% or a glycerol solution with a mass fraction of 3-15%.

8. The method for preparing the medicinal pregelatinized starch according to claim 1, characterized in that: In step 2, the mass ratio of polyol to starch slurry is 0.15~0.3:

1.

9. The medicinal pregelatinized starch prepared by the preparation method according to any one of claims 1 to 8.

10. Use of the medicinal pregelatinized starch prepared by the preparation method according to any one of claims 1 to 8 in the preparation of a drug, wherein the drug is an oral preparation selected from tablets or capsules.

Images