A stabilized lyophilized oral preparation of phloroglucinol and its preparation method

Abstract

The present invention relates to the technical field of lyophilized oral preparations of phloroglucinol, and specifically discloses a stabilized lyophilized oral preparation of phloroglucinol and a preparation method thereof. The above-mentioned stabilized lyophilized oral preparation of phloroglucinol, its raw materials include by mass: 50-60 parts of phloroglucinol, 5-8 parts of polyvinyl alcohol, 1-3 parts of ε-polylysine, 1-2 parts of surfactant, 30-40 parts of mannitol, and 1-3 parts of sweetener. The present invention not only improves product stability, long-term storage, and stable content of active pharmaceutical ingredients, but also can quickly absorb water and swell after disintegration in the oral cavity, has a fast disintegration rate, high dissolution efficiency, significantly improves the therapeutic effect of the drug, and has a fast dissolution rate, good taste, and expands the scope of application.

Description

Technical Field

[0001] The invention relates to the technical field of lyophilized oral preparations of phloroglucinol, and in particular to a stabilized lyophilized oral preparation of phloroglucinol and a preparation method thereof. Background Art

[0002] Phloroglucinol is a smooth muscle antispasmodic drug, mainly used for acute spasmodic pain. Phloroglucinol is suitable for acute spasmodic pain caused by digestive system and biliary dysfunction; acute spasmodic urethral, ​​bladder, and renal colic; gynecological spasmodic pain. Phloroglucinol also has a wide range of application prospects in alleviating the pain of natural childbirth. Research results show that phloroglucinol injection can significantly shorten the delivery time, accelerate the cervical dilation, shorten the delivery time, and thus relieve the pain of the parturient.

[0003] Phloroglucinol is a myotropic, non-atropine, non-opioid pure smooth muscle spasmolytic. Compared with other smooth muscle spasmolytics, it has very few allergic reactions and does not cause changes in blood pressure and heart rate. Currently, phloroglucinol is available in two dosage forms: oral lyophilized preparations and injections. Since oral lyophilized preparations are more convenient to use, they are currently being widely promoted and used.

[0004] The existing oral freeze-dried preparation of phloroglucinol is prone to oxidation and poor stability due to its structural characteristics. The drug is easy to break and lose powder, has a high breakage rate, is inconvenient to carry, and has poor drug dissolution effect and slow onset of effect.

[0005] How to prepare a freeze-dried oral preparation that is not only stable but also not prone to powdering, has fast drug dissolution and fast onset of action has excellent research prospects. Summary of the invention

[0006] The purpose of the present invention is to solve the shortcomings of the prior art and to propose a stabilized lyophilized oral preparation of phloroglucinol and a preparation method thereof.

[0007] A stabilized lyophilized oral preparation of phloroglucinol comprises the following raw materials by mass: 50-60 parts of phloroglucinol, 5-8 parts of polyvinyl alcohol, 1-3 parts of epsilon-polylysine, 1-2 parts of a surfactant, 30-40 parts of mannitol and 1-3 parts of a sweetener.

[0008] Preferably, the raw materials include, by mass: 52 parts of phloroglucinol, 6.5 parts of polyvinyl alcohol, 2 parts of ε-polylysine, 1.5 parts of surfactant, 37 parts of mannitol, and 1 part of sweetener.

[0009] Preferably, the particle size D90 of phloroglucinol is ≤5 μm.

[0010] Preferably, the surfactant is sorbitan fatty acid ester and / or polyoxyethylene sorbitan fatty acid ester.

[0011] Preferably, the sweetener is at least one of cyclamate, sucralose, aspartame, sucrose, glucose and stevioside.

[0012] The preparation method of the stabilized lyophilized oral preparation of phloroglucinol comprises the following steps:

[0013] S1, adding polyvinyl alcohol and ε-polylysine to an ethanol aqueous solution and stirring evenly, adding phloroglucinol and a surfactant thereto in sequence under stirring, and continuing stirring to obtain a preform a;

[0014] S2, adding preform a dropwise to the liquid paraffin in a stirring state, stirring for 10-30 min after the addition is complete, cooling to -20 to -30 ° C, keeping warm for 10-20 min, warming to room temperature, allowing the system to stand for stratification, recovering the upper layer of liquid paraffin, adding mannitol and sweetener, stirring for 1-2 h, ultrasonically degassing, and pouring into a mold to obtain preform b;

[0015] S3. Cool the preform b to -20 to -40°C, pre-freeze for 1-2 hours, continue to cool to -40 to -50°C, and keep warm for 1-2 hours; evacuate the system to a vacuum degree of 5-20Pa, then warm to room temperature, and freeze-dry to obtain a lyophilized oral preparation of phloroglucinol.

[0016] Preferably, in S1, the mass fraction of the ethanol aqueous solution is 60-80%.

[0017] Preferably, in S3, the freeze-drying temperature is -40 to -60°C, and the freeze-drying time is 5 to 10 hours.

[0018] Beneficial effects:

[0019] The stabilized lyophilized oral preparation of phloroglucinol obtained by the present invention can disintegrate and release the drug under the tongue within 10 seconds, has a rapid onset of drug action, high bioavailability, can significantly reduce side effects, and reduce irritation to the digestive tract mucosa. At the same time, the toughness of the lyophilized preparation can be significantly increased, and it is not easy to fall off, thus solving the problem of easy falling of powder in traditional lyophilized tablets.

[0020] Polyvinyl alcohol is very likely to cause adhesion of latex particles due to its high viscosity, and has poor coating properties for phloroglucinol. The present invention uses polyvinyl alcohol and ε-polylysine to compound, so that the size of the obtained microspheres is stable, wherein ε-polylysine is a highly branched three-dimensional structure, has a large number of branching points in its molecular structure, the molecular chain is not easy to entangle, has good dispersibility with polyvinyl alcohol, and the latex particles are not easy to adhere. After freezing treatment, not only the molecular structure is regularly arranged, but also hydrogen bonds are formed with polyvinyl alcohol to form a stable network structure, which can significantly enhance the stability of phloroglucinol, and at the same time has good antibacterial properties, greatly extending the protection period of the preparation.

[0021] The results of experiments show that the invention not only improves product stability, ensures long-term storage, and stabilizes the content of active drug ingredients, but also can quickly absorb water and swell after disintegrating in the oral cavity, has a fast disintegration speed, and a high dissolution efficiency, thus significantly improving the therapeutic effect of the drug. It also has a fast dissolution speed, a good taste, and a wider range of applications.

[0022] The invention has good taste, simple preparation process, good stability and is easy for industrial mass production. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 The stability comparison chart of the stabilized lyophilized oral preparation of phloroglucinol obtained in Example 5 and Comparative Examples 1-2 is shown.

[0024] Figure 2 This is a comparison chart of the disintegration time of the stabilized lyophilized oral preparations of phloroglucinol obtained in Example 5 and Comparative Examples 1-2 after being stored under different conditions for 10 days.

[0025] Figure 3 The dissolution curves of the stabilized lyophilized oral preparations of phloroglucinol obtained in Example 5 and Comparative Examples 1-2 in artificial saliva are shown. DETAILED DESCRIPTION

[0026] The present invention will be further explained below in conjunction with specific embodiments.

[0027] Example 1

[0028] A stabilized lyophilized oral preparation of phloroglucinol comprises raw materials of 50 kg of phloroglucinol, 5 kg of polyvinyl alcohol, 1 kg of ε-polylysine, 1 kg of a surfactant, 30 kg of mannitol and 1 kg of a sweetener.

[0029] The preparation method of the stabilized lyophilized oral preparation of phloroglucinol comprises the following steps:

[0030] S1. Add polyvinyl alcohol and ε-polylysine to 15 kg of 60% ethanol aqueous solution and stir evenly. Add phloroglucinol and Span 60 in sequence under stirring, continue stirring for 1 hour at a stirring speed of 500 r / min to obtain preform a.

[0031] S2, add preform a dropwise to 30 kg of liquid paraffin in a stirring state at a stirring speed of 4000 r / min, continue stirring for 10 min after the addition is complete, cool to -20 ° C, keep warm for 10 min, warm to room temperature, let the system stand for stratification, recover the upper layer of liquid paraffin, add mannitol and sodium cyclamate, stir for 1 h, degas by ultrasonication, and pour into a mold to obtain preform b;

[0032] S3. Cool the preform b to -20°C, pre-freeze for 1 hour, continue to cool to -40°C, keep warm for 1 hour, evacuate the system to a vacuum degree of 5Pa, warm to room temperature, and freeze-dry at -40°C for 5 hours.

[0033] Example 2

[0034] A stabilized lyophilized oral preparation of phloroglucinol comprises raw materials of 60 kg of phloroglucinol, 8 kg of polyvinyl alcohol, 3 kg of ε-polylysine, 2 kg of a surfactant, 40 kg of mannitol and 3 kg of a sweetener.

[0035] The preparation method of the stabilized lyophilized oral preparation of phloroglucinol comprises the following steps:

[0036] S1, adding polyvinyl alcohol and ε-polylysine to 20 kg of 80% ethanol aqueous solution and stirring evenly, adding phloroglucinol and Span 60 thereto in sequence under stirring, and continuing stirring for 2 hours at a stirring speed of 1000 r / min to obtain preform a;

[0037] S2, preform a was added dropwise to 40 kg of liquid paraffin in a stirring state at a stirring speed of 6000 r / min. After the addition was complete, stirring was continued for 30 min, the temperature was lowered to -30 ° C, kept warm for 20 min, and then warmed to room temperature. The system was allowed to stand for stratification, the upper layer of liquid paraffin was recovered, mannitol and aspartame were added, stirred for 2 h, ultrasonically degassed, and poured into a mold to obtain preform b;

[0038] S3, cool the preform b to -40°C, pre-freeze for 2h, continue to cool to -50°C, keep warm for 2h, evacuate to the system vacuum degree of 20Pa, warm to room temperature, freeze-dry at -60°C for 10h, and re-press.

[0039] Example 3

[0040] A stabilized lyophilized oral preparation of phloroglucinol comprises raw materials of 52 kg of phloroglucinol, 5.5 kg of polyvinyl alcohol, 1.2 kg of ε-polylysine, 1.2 kg of a surfactant, 33 kg of mannitol and 1.2 kg of a sweetener.

[0041] The preparation method of the stabilized lyophilized oral preparation of phloroglucinol comprises the following steps:

[0042] S1. Add polyvinyl alcohol and ε-polylysine to 17 kg of 75% ethanol aqueous solution and stir evenly. Add phloroglucinol and Tween 60 in sequence under stirring, continue stirring for 80 min at a stirring speed of 900 r / min to obtain preform a.

[0043] S2, preform a was added dropwise to 33 kg of liquid paraffin in a stirring state at a stirring speed of 5500 r / min. After the addition was complete, stirring was continued for 15 min, the temperature was lowered to -28 ° C, kept warm for 13 min, and then heated to room temperature. The system was allowed to stand for stratification, the upper layer of liquid paraffin was recovered, mannitol and sucrose were added, and stirred for 100 min, ultrasonically degassed, and poured into a mold to obtain preform b;

[0044] S3, cool the preform b to -25°C, pre-freeze for 100 min, continue to cool to -43°C, keep warm for 100 min, evacuate the system to a vacuum degree of 10 Pa, warm to room temperature, freeze-dry at -45°C for 9 h, and re-press.

[0045] Example 4

[0046] A stabilized lyophilized oral preparation of phloroglucinol comprises raw materials of 56 kg of phloroglucinol, 7.2 kg of polyvinyl alcohol, 2.5 kg of ε-polylysine, 1.8 kg of a surfactant, 38 kg of mannitol and 2.4 kg of a sweetener.

[0047] The preparation method of the stabilized lyophilized oral preparation of phloroglucinol comprises the following steps:

[0048] S1. Add polyvinyl alcohol and ε-polylysine to 19 kg of 65% ethanol aqueous solution and stir evenly. Add phloroglucinol and Tween 80 thereto in sequence under stirring. Continue stirring for 100 min at a stirring speed of 700 r / min to obtain preform a.

[0049] S2, adding preform a dropwise to 37 kg of liquid paraffin in a stirring state at a stirring speed of 4500 r / min, continuing stirring for 25 min after the addition is complete, cooling to -22°C, keeping warm for 17 min, heating to room temperature, allowing the system to stand for stratification, recovering the upper layer of liquid paraffin, adding mannitol and sucralose, stirring for 80 min, ultrasonically degassing, and pouring into a mold to obtain preform b;

[0050] S3, cool the preform b to -35°C, pre-freeze for 80 minutes, continue to cool to -47°C, keep warm for 80 minutes, evacuate the system to a vacuum degree of 18Pa, warm to room temperature, freeze-dry at -55°C for 7 hours, and re-press.

[0051] Example 5

[0052] A stabilized lyophilized oral preparation of phloroglucinol comprises raw materials of 52 kg of phloroglucinol, 6.5 kg of polyvinyl alcohol, 2 kg of ε-polylysine, 1.5 kg of a surfactant, 37 kg of mannitol and 1 kg of a sweetener.

[0053] The preparation method of the stabilized lyophilized oral preparation of phloroglucinol comprises the following steps:

[0054] S1. Add polyvinyl alcohol and ε-polylysine to 18 kg of 70% ethanol aqueous solution and stir evenly. Add phloroglucinol and Tween 80 in sequence under stirring, continue stirring for 90 min at a stirring speed of 800 r / min to obtain preform a.

[0055] S2, adding preform a dropwise to 35 kg of liquid paraffin in a stirring state at a stirring speed of 5000 r / min, continuing stirring for 20 min after the addition is complete, cooling to -25°C, keeping warm for 15 min, warming to room temperature, allowing the system to stand for stratification, recovering the upper layer of liquid paraffin, adding mannitol and sucralose, stirring for 90 min, ultrasonically degassing, and pouring into a mold to obtain preform b;

[0056] S3, cool the preform b to -30°C, pre-freeze for 90 minutes, continue to cool to -45°C, keep warm for 90 minutes, evacuate the system to a vacuum degree of 15Pa, warm to room temperature, and freeze-dry at -50°C for 8 hours.

[0057] Comparative Example 1

[0058] A stabilized lyophilized oral preparation of phloroglucinol comprises raw materials of 52 kg of phloroglucinol, 6.5 kg of polyvinyl alcohol, 1.5 kg of a surfactant, 37 kg of mannitol and 1 kg of a sweetener.

[0059] The preparation method of the stabilized lyophilized oral preparation of phloroglucinol comprises the following steps:

[0060] S1. Add polyvinyl alcohol to 18 kg of 70% ethanol aqueous solution and stir evenly. Add phloroglucinol and Tween 80 in sequence under stirring. Continue stirring for 90 min at a stirring speed of 800 r / min to obtain preform a.

[0061] S2, adding preform a dropwise to 35 kg of liquid paraffin in a stirring state at a stirring speed of 5000 r / min, continuing stirring for 20 min after the addition is complete, cooling to -25°C, keeping warm for 15 min, warming to room temperature, allowing the system to stand for stratification, recovering the upper layer of liquid paraffin, adding mannitol and sucralose, stirring for 90 min, ultrasonically degassing, and pouring into a mold to obtain preform b;

[0062] S3, cool the preform b to -30°C, pre-freeze for 90 minutes, continue to cool to -45°C, keep warm for 90 minutes, evacuate the system to a vacuum degree of 15Pa, warm to room temperature, and freeze-dry at -50°C for 8 hours.

[0063] Comparative Example 2

[0064] A stabilized lyophilized oral preparation of phloroglucinol comprises raw materials of 52 kg of phloroglucinol, 6.5 kg of polyvinyl alcohol, 2 kg of ε-polylysine, 1.5 kg of a surfactant, 37 kg of mannitol and 1 kg of a sweetener.

[0065] The preparation method of the stabilized lyophilized oral preparation of phloroglucinol comprises the following steps:

[0066] S1. Add polyvinyl alcohol and ε-polylysine to 18 kg of 70% ethanol aqueous solution and stir evenly. Add phloroglucinol and Tween 80 in sequence under stirring, continue stirring for 90 min at a stirring speed of 800 r / min to obtain preform a.

[0067] S2, adding preform a dropwise to 35 kg of liquid paraffin in a stirring state at a stirring speed of 5000 r / min, continuing stirring for 20 min after the addition is complete, cooling to -25°C, keeping warm for 15 min, warming to room temperature, allowing the system to stand for stratification, recovering the upper layer of liquid paraffin, adding mannitol and sucralose, stirring for 90 min, ultrasonically degassing, and pouring into a mold to obtain preform b;

[0068] S3. Freeze-dry the preform b at -50°C for 8 h.

[0069] With reference to the drug stability test method specified in Appendix II of the Pharmacopoeia of the People's Republic of China (2010 Edition), the content of the stabilized lyophilized oral preparations of phloroglucinol obtained in Example 5 and Comparative Examples 1-2 was measured after being stored for 10 days under different conditions.

[0070] like Figure 1 As shown, the content of the stabilized lyophilized oral preparation of phloroglucinol obtained in Example 5 is the most stable.

[0071] The disintegration time of each group of lyophilized oral preparations of phloroglucinol stored for 10 days under the above different conditions was measured as follows: the same mass of each group of samples were placed in a test tube with appropriate amount of warm water (37±1℃), and the time was started with a stopwatch until the tablets were completely disintegrated and passed through the No. 2 sieve. If necessary, appropriate amount of water can be added to quickly rinse the sieve. Each group of samples was checked 10 times.

[0072] like Figure 2 As shown, the disintegration time of the stabilized lyophilized oral preparation of phloroglucinol obtained in Example 5 changed the least, which was better than that of Comparative Examples 1-2 (P < 0.05).

[0073] The stabilized lyophilized oral preparations of phloroglucinol obtained in Example 5 and Comparative Examples 1-2 were placed in 1000 mL of artificial saliva (Legen Biotechnology, model CZ0260, pH=6.8) at a temperature of 37±0.5°C, and the paddle method speed was 50 rpm to measure the dissolution of each group.

[0074] like Figure 3 As shown, the solubility of the stabilized lyophilized oral preparation of phloroglucinol obtained in Example 5 reached more than 95% at 5 minutes, which was significantly better than that of Comparative Examples 1-2 (P < 0.05), and was more conducive to rapid onset of effect.

[0075] The applicant believes that this is because the present invention uses polyvinyl alcohol and ε-polylysine to compound, so that the size of the obtained microspheres is stable, wherein ε-polylysine is a highly branched three-dimensional structure, and its molecular structure has a large number of branching points, the molecular chain is not easy to entangle, and the dispersion with polyvinyl alcohol is good, and the emulsion particles are not easy to adhere. After freezing treatment, not only the molecular structure is arranged regularly, but also hydrogen bonds with polyvinyl alcohol to form a stable network structure, which can significantly enhance the stability of phloroglucinol, and at the same time, the antibacterial property is good, and the protection period of the preparation is greatly extended. The present invention not only improves the product stability, long-term storage, and stable content of active pharmaceutical ingredients, but also can quickly absorb water and swell after disintegration in the oral cavity, has a fast disintegration rate, high dissolution efficiency, significantly improves the drug treatment effect, and has a fast dissolution rate, good taste, and expands the scope of application.

[0076] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A freeze-dried oral preparation of phloroglucinol, characterized in that: The raw materials include, by mass: 50-60 parts of phloroglucinol, 5-8 parts of polyvinyl alcohol, 1-3 parts of ε-polylysine, 1-2 parts of surfactant, 30-40 parts of mannitol, and 1-3 parts of sweetener; The surfactant is sorbitan fatty acid ester and / or polyoxyethylene sorbitan fatty acid ester; The sweetener is at least one of cyclamate, sucralose, aspartame, sucrose, glucose and stevioside; Prepared by the following steps: S1, adding polyvinyl alcohol and ε-polylysine to an ethanol aqueous solution and stirring evenly, adding phloroglucinol and a surfactant thereto in sequence under stirring, and continuing stirring to obtain a preform a; S2, adding preform a dropwise to the liquid paraffin in a stirring state, stirring for 10-30 min after the addition is complete, cooling to -20 to -30 ° C, keeping warm for 10-20 min, warming to room temperature, allowing the system to stand for stratification, recovering the upper layer of liquid paraffin, adding mannitol and sweetener, stirring for 1-2 h, ultrasonically degassing, and pouring into a mold to obtain preform b; S3. Cool the preform b to -20 to -40°C, pre-freeze for 1-2 hours, continue to cool to -40 to -50°C, and keep warm for 1-2 hours; evacuate the system to a vacuum degree of 5-20Pa, then warm to room temperature, and freeze-dry to obtain a lyophilized oral preparation of phloroglucinol.

2. The lyophilized oral preparation of phloroglucinol according to claim 1, characterized in that: The particle size of phloroglucinol is D90≤5μm.

3. The lyophilized oral preparation of phloroglucinol according to claim 1, characterized in that: The raw materials include, by weight: 52 parts of phloroglucinol, 6.5 parts of polyvinyl alcohol, 2 parts of epsilon-polylysine, 1.5 parts of a surfactant, 37 parts of mannitol and 1 part of a sweetener.

4. A method for preparing the lyophilized oral preparation of phloroglucinol according to any one of claims 1 to 3, characterized in that: The steps include: S1, adding polyvinyl alcohol and ε-polylysine to an ethanol aqueous solution and stirring evenly, adding phloroglucinol and a surfactant thereto in sequence under stirring, and continuing stirring to obtain a preform a; S2, adding preform a dropwise to the liquid paraffin in a stirring state, stirring for 10-30 min after the addition is complete, cooling to -20 to -30 ° C, keeping warm for 10-20 min, warming to room temperature, allowing the system to stand for stratification, recovering the upper layer of liquid paraffin, adding mannitol and sweetener, stirring for 1-2 h, ultrasonically degassing, and pouring into a mold to obtain preform b; S3. Cool the preform b to -20 to -40°C, pre-freeze for 1-2 hours, continue to cool to -40 to -50°C, and keep warm for 1-2 hours; evacuate the system to a vacuum degree of 5-20Pa, then warm to room temperature, and freeze-dry to obtain a lyophilized oral preparation of phloroglucinol.

5. The method for preparing the lyophilized oral preparation of phloroglucinol according to claim 4, characterized in that: In S1, the mass fraction of the ethanol aqueous solution is 60-80%.

6. The method for preparing the lyophilized oral preparation of phloroglucinol according to claim 4, characterized in that: In S3, the freeze-drying temperature is -40 to -60°C, and the freeze-drying time is 5 to 10 hours.

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