Sustained-release acyclovir tablet and preparation process thereof

Abstract

The present application relates to a kind of sustained-release acyclovir tablets and its preparation process, belong to the technical field of medicine.The acyclovir tablet provided by the present application has immediate-release layer and sustained-release layer, immediate-release layer can be quickly released, rapidly increase the blood concentration in human body;Sustained-release layer has multi-stage drug release characteristics, it includes three kinds of sustained-release particles, which can effectively delay, positioning release drug, constantly supplement the blood concentration in body, maintain stable blood concentration, can effectively sustain release up to about 12h, and can maintain relatively stable blood concentration within 12 hours, reduce the frequency of drug taking, improve patient compliance, suitable for the patient with herpes simplex virus infection who needs long-term treatment.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical technology, in particular to a sustained-release acyclovir tablet and a preparation process thereof. BACKGROUND

[0002] Acyclovir, as a representative of open-loop nucleoside antiviral drugs, has become the core drug for the clinical treatment of herpes virus infection since it was first synthesized in 1977. Its unique chemical structure and mechanism of action make it occupy an important position in the field of antiviral drugs.

[0003] Acyclovir, also known as 9-(2-hydroxyethoxymethyl) guanine, has the molecular formula C8H 11 N5O3, and its physical properties are white crystalline powder, melting point 256-257℃, slightly soluble in water, slightly soluble in glacial acetic acid or hot water, but easily soluble in dilute sodium hydroxide solution.

[0004] Acyclovir inhibits viral DNA synthesis by specific inhibition, and is the first choice for the treatment of various herpes virus infections. For herpes simplex virus (HSV) infection, the existing clinical drug administration mode significantly shortens the course of genital herpes and oral herpes caused by HSV-1 and HSV-2 through oral administration (200mg / time, once every 4 hours) or intravenous administration (5mg / kg, once every 8 hours). The bioavailability of oral drugs is 15-30%, and more than 90% of the original form is excreted through glomerular filtration and renal tubular secretion, with a half-life of 2.5 hours. Therefore, the drug is used frequently in clinical practice, up to 5 times a day.

[0005] The prior art CN115463102A discloses an acyclovir tablet and a preparation method thereof, which solves the problem of tablet weight difference, but the preparation still belongs to a rapid-release oral preparation and cannot meet the clinical demand for reducing the frequency of drug administration.

[0006] It can be seen that the prior art still has the technical problems of frequent drug administration, inconvenience of use, and large variation of blood drug concentration. SUMMARY

[0007] The present application aims to overcome the shortcomings of the prior art and provide a sustained-release acyclovir tablet and a preparation process thereof.

[0008] To achieve the above-mentioned purpose, the technical solution adopted by the present application is as follows:

[0009] In a first aspect, the present application provides a sustained-release acyclovir tablet, which comprises the following components by weight:

[0010] An extended-release acyclovir tablet comprising the following components in the weight parts: the weight parts ratio of the immediate-release layer to the extended-release layer is (2-4):(3-8).

[0011] A: immediate-release layer

[0012] Active ingredient: acyclovir 130-300 parts,

[0013] Diluent: 100-200 parts,

[0014] Disintegrant: low-substituted hydroxypropyl cellulose 10-30 parts,

[0015] Binder: cross-linked polyvidone (K30) 5-20 parts,

[0016] Lubricant: 1-5 parts,

[0017] The diluent is selected from at least one of sucrose, starch, lactose, and microcrystalline cellulose,

[0018] The lubricant is selected from at least one of magnesium stearate, microfine silica, and talc.

[0019] B: extended-release layer

[0020] The extended-release layer is composed of extended-release granule 1, extended-release granule 2, and extended-release granule 3 in a mass ratio of 2:(1-2):(1-2);

[0021] Active ingredient: acyclovir 150-300 parts,

[0022] Extended-release matrix: hypromellose K100M 100-200 parts,

[0023] Binder: hypromethylcellulose E6LV 10-25 parts,

[0024] Lubricant: magnesium stearate 3-5 parts,

[0025] Enteric film: Eudragit S100 30-50 parts,

[0026] Film-forming modifier: sodium ethylenediaminetetraacetate 3-5 parts,

[0027] Plasticizer: triethyl citrate (TEC) 2-5 parts,

[0028] Extended-release granule 1 is not coated with an enteric film, extended-release granule 2 is prepared by coating extended-release granule 1 with an enteric film at 3-5% of the weight of the granule; and extended-release granule 3 is prepared by coating extended-release granule 1 with an enteric film at 7-9% of the weight of the granule.

[0029] The weight parts ratio of the immediate-release layer to the extended-release layer is preferably 2:(5-8).

[0030] The sustained-release layer is composed of sustained-release granule 1, sustained-release granule 2, and sustained-release granule 3 in a preferred mass ratio of 2:(1.5-2):(1.5-2).

[0031] In another aspect, the present application provides a preparation process of the sustained-release acyclovir tablet.

[0032] Preparation of A immediate-release layer granule:

[0033] A1: Put the main drug, diluent, and disintegrant into a pulverizer and sieve through a 100-mesh screen; add a water solution of the binder to mix into a soft material, sieve through an 18-mesh screen to granulate;

[0034] A2: Put the wet granule into a dryer to make the dry granule have a water content within a specified range; sieve the dried granule through an 18-mesh screen to size;

[0035] A3: Add the sized granule to the lubricant to mix uniformly to obtain the immediate-release layer granule.

[0036] B: Preparation of the sustained-release layer (sustained-release granule 1, sustained-release granule 2, and sustained-release granule 3)

[0037] B1: Put the main drug and sustained-release matrix into a pulverizer to pulverize and mix, sieve through a 100-mesh screen; add a water solution of the binder (hydroxypropyl methyl cellulose E6LV) to mix into a soft material, add the soft material into an extrusion roller compactor, set the extrusion aperture to 0.6 mm and the extrusion speed to 30 rpm, and dry to obtain the sustained-release granule 1 having a water content of 2%.

[0038] B2: Preparation of enteric coating: prepare an enteric coating solution by using 95% ethanol to prepare the prescription amount of enteric material, set the fluidized bed air inlet temperature to 35°C, control the temperature of the sustained-release granule 1 to 35°C, adjust the appropriate parameters, control the coating weight gain to 4%, and prepare the sustained-release granule 2; control the coating weight gain to 8% to prepare the sustained-release granule 3.

[0039] B3: Mix the sustained-release granule 1, 2, and 3 according to the weight ratio, add the lubricant magnesium stearate, and obtain the sustained-release layer mixed sustained-release granule.

[0040] C: Tabletting

[0041] Tablet the immediate-release layer granule and the sustained-release layer mixed sustained-release granule according to the weight ratio. The weight ratio of the immediate-release layer to the sustained-release layer is (2-4):(3-8).

[0042] In another aspect, the present application provides the use of the aforementioned sustained-release acyclovir tablet and the sustained-release acyclovir tablet prepared by the process in the preparation of a medicament for treating herpes virus infection, especially for long-term treatment of herpes virus infection.

[0043] The application provides a sustained-release acyclovir tablet and a preparation process thereof. The prepared acyclovir tablet has a quick-release layer and a sustained-release layer; the quick-release layer can quickly release and rapidly increase the blood drug concentration in the human body; however, considering that the half-life of the acyclovir tablet is only about 2.5 h, in order to improve the applicability of the human body, reduce the frequency of taking medicine and maintain the stable blood drug concentration, the sustained-release layer of the sustained-release acyclovir tablet provided by the application has a multi-stage drug release characteristic, which comprises uncoated sustained-release granules and enteric sustained-release granules; the uncoated sustained-release granules and the enteric sustained-release granules can effectively cooperate with the drug release of the quick-release layer, release the drug in a time-delayed and positioning manner, continuously supplement the blood drug concentration in the body and maintain the stability of the blood drug concentration.

[0044] The effective drug release time of the sustained-release granules and the time-delayed release time of the coating correspond to the half-life of acyclovir in the human body (2.5 h), and are controlled to be about 2-3 h; the multi-stage timing release of the drug in the sustained-release layer effectively cooperates with the metabolism of the drug in the human body and can achieve the technical effect of maintaining the stability of the blood drug concentration; the long-time maintenance of the stability of the blood drug concentration is beneficial to the long-term treatment of herpes virus infection. BRIEF DESCRIPTION OF DRAWINGS

[0045] Figure 1 Cumulative drug release degree comparison chart of examples 1-3 and comparative example 4.

[0046] Figure 2 Cumulative drug release degree comparison chart of example 3 and comparative examples 1-3.

[0047] Figure 3 Blood drug concentration-time curve chart of example 3 and comparative example 3. DETAILED DESCRIPTION

[0048] In order to better illustrate the purpose, technical scheme and advantages of the application, the application will be further described below in combination with specific examples.

[0049] Acyclovir tablet: 200 mg / tablet, commercially available reference preparation, produced by a certain brand in Japan.

[0050] Other materials, reagents and the like used in the examples can be obtained from commercial channels unless otherwise specified.

[0051] Example 1

[0052] A sustained-release acyclovir tablet comprises the following components in parts by weight:

[0053] A: quick-release layer

[0054] Main drug: acyclovir 150 parts,

[0055] Diluent: sucrose 100 parts,

[0056] Disintegrant: low-substitution hydroxypropyl cellulose 15 parts,

[0057] Binder: cross-linked povidone (K30) 10 parts,

[0058] Lubricant: magnesium stearate 1.5 parts;

[0059] Preparation of A immediate-release layer granules:

[0060] A1: Put the main drug (acyclovir), diluent (sucrose), and disintegrant (low-substituted hydroxypropyl cellulose) into a pulverizer and sieve through a 100-mesh screen. Add a binder (K30) aqueous solution and mix to form a soft material. Sieve the soft material through an 18-mesh screen to form granules.

[0061] A2: Put the wet granules into a dryer to bring the moisture content of the dry granules to the specified range of 2%. Sieve the dried granules through an 18-mesh screen to form granules.

[0062] A3: Add a lubricant (magnesium stearate) to the sieved granules and mix them evenly to obtain immediate-release layer granules.

[0063] B: sustained-release layer

[0064] Main drug: acyclovir 170 parts,

[0065] Sustained-release matrix: hypromellose K100M 120 parts,

[0066] Binder: hypromellose E6LV 15 parts,

[0067] Lubricant: magnesium stearate 3 parts,

[0068] Enteric film: Eudragit S100 30 parts,

[0069] Film-forming modifier: sodium ethylenediaminetetraacetate 4 parts,

[0070] Plasticizer: triethyl citrate (TEC) 3 parts.

[0071] Preparation of sustained-release granules:

[0072] B1: Put the main drug and sustained-release matrix into a pulverizer and mix them, then sieve through a 100-mesh screen. Add a binder (hypromellose E6LV) aqueous solution and mix to form a soft material. Add the soft material to an extrusion roller compactor, set the extrusion aperture to 0.6 mm, and set the extrusion speed to 30 rpm. Dry the extruded material to a moisture content of 2% to obtain sustained-release granules 1.

[0073] B2: Preparation of enteric coating: Prepare an enteric coating solution by dissolving the prescribed amount of enteric material in 95% ethanol. Set the fluidized bed inlet temperature to 35°C and control the temperature of the sustained-release granules 1 to 35°C. Adjust the parameters as appropriate, control the coating weight gain to 4%, and prepare sustained-release granules 2. Control the coating weight gain to 8% and prepare sustained-release granules 3.

[0074] B3: The sustained release granules 1, 2, 3 are mixed in a ratio of 2:1.5:1.5 by weight, and a lubricant, magnesium stearate, is added to obtain the sustained release layer mixed sustained release granules.

[0075] C: Compression of tablets

[0076] The immediate release layer granules and the sustained release layer mixed sustained release granules are compressed in a ratio of 2:5 by weight to obtain a double layer tablet (specification: 200 mg / tablet).

[0077] Example 2

[0078] A: Immediate release layer

[0079] Drug substance: Aciclovir 210 parts,

[0080] Diluent: Sucrose 140 parts,

[0081] Disintegrant: Low-substituted hydroxypropyl cellulose 20 parts,

[0082] Binder: Cross-linked polyvidone (K30) 12 parts,

[0083] Lubricant: Magnesium stearate 1.5 parts;

[0084] B: Sustained release layer

[0085] Drug substance: Aciclovir 190 parts,

[0086] Sustained release matrix: Hypromellose K100M 130 parts,

[0087] Binder: Hypromellose E6LV 20 parts,

[0088] Lubricant: Magnesium stearate 4 parts,

[0089] Enteric film: Eudragit S100 30 parts,

[0090] Film forming modifier: Sodium ethylenediaminetetraacetate 4 parts,

[0091] Plasticizer: Triethyl citrate (TEC) 3 parts.

[0092] Preparation method is the same as Example 1.

[0093] Example 3

[0094] A: Immediate release layer

[0095] Drug substance: Aciclovir 300 parts,

[0096] Diluent: Sucrose 200 parts,

[0097] Disintegrant: Low-substituted hydroxypropyl cellulose 30 parts,

[0098] Binder: Cross-linked polyvidone (K30) 20 parts,

[0099] Lubricant: magnesium stearate 2 parts;

[0100] B: sustained release layer

[0101] Active ingredient: acyclovir 200 parts,

[0102] Sustained release matrix: hypromellose K100M 140 parts,

[0103] Binder: hypromellose E6 LV 25 parts,

[0104] Lubricant: magnesium stearate 5 parts,

[0105] Enteric film: Eudragit S100 30 parts,

[0106] Film forming modifier: sodium ethylenediaminetetraacetate 4 parts,

[0107] Plasticizer: triethyl citrate (TEC) 3 parts.

[0108] Preparation method is the same as Example 1.

[0109] Comparative Example 1

[0110] Comparative Example 1 is the same as Example 3, except that sustained release granule 3 is replaced by sustained release granule 2 (the prepared tablet sustained release layer only has secondary sustained release function).

[0111] Comparative Example 2

[0112] Comparative Example 2 is the same as Example 3, except that sustained release granules 2, 3 are replaced by sustained release granule 1 (the prepared tablet sustained release layer only has primary sustained release function).

[0113] Comparative Example 3

[0114] Comparative Example 3 is the same as Example 3, except that the enteric coating does not contain sodium ethylenediaminetetraacetate.

[0115] Comparative Example 4

[0116] Commercially available preparation reference preparation.

[0117] Table 1 Formulation of pharmaceutical preparations of Examples 1-3 and Comparative Examples 1-3.

[0118]

[0119]

[0120] I. In vitro release test

[0121] According to the dissolution determination method of the second part of the People's Republic of China Pharmacopoeia Appendix, the blue shift method was selected to determine the dissolution; the dissolution medium was kept at 37℃. Simulate the drug release environment in the stomach: pH 1.0 hydrochloric acid solution medium. Simulate the drug release environment in the intestine: pH 6.8 phosphate buffer. Record the cumulative drug release rate (%) at 5 min, 10 min, 0.5 h, 1.5 h, 2 h (replace the pH 6.8 phosphate buffer immediately after sampling the pH 1.0 hydrochloric acid solution medium), 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, respectively, as shown in Table 2.

[0122] Table 2 Cumulative drug release rate (%)

[0123]

[0124]

[0125] From the in vitro release test, it can be known that the acyclovir tablets prepared in Examples 1-3 can release 26.1% of the drug within 10 minutes, which indicates that the immediate-release layer can disintegrate quickly, indicating that the blood drug concentration in the human body can be rapidly increased; the sustained-release layer can release the drug in different time periods due to the inclusion of sustained-release granules 1, 2 and 3, and the drug can be effectively released for 11-12 h. Comparative Example 1 contains sustained-release granules 1 and 2, and Comparative Example 2 contains sustained-release granule 1. From the in vitro release data of Comparative Example 2 containing only sustained-release granule 1, it can be known that the sustained-release granule 1 has good sustained-release effect within 0-3 h, and the cumulative drug release amount is nearly 87.2% at 3 h, which indicates that the effective sustained-release effect of the sustained-release granule 1 can be maintained for about 3 h. By comparing Comparative Example 1 with Comparative Example 2, it can be known that the sustained-release granule 2 starts to release the drug at nearly 4-5 h, which indicates that the enteric-coated sustained-release granule 2 can be dissolved in the simulated intestinal fluid (pH 6.8) for 2-3 hours. By comparing Example 3 with Comparative Example 2, it can be known that the sustained-release granule 3 starts to release the drug at nearly 7-8 h, which indicates that the enteric-coated sustained-release granule 2 can be dissolved in the simulated intestinal fluid (pH 6.8) for 5-6 hours. By comparing Example 3 with Comparative Example 3, it can be known that the lack of film-forming modifier in the coating component will cause the sustained-release granules 2 and 3 to release prematurely, resulting in an effective sustained-release time of only 7-8 h, which is difficult to maintain a stable blood drug concentration for a long time.

[0126] In summary, the effective drug release time of the sustained-release granule and the time release time of the coating correspond to the half-life of acyclovir in the human body, which is 2.5 h, and the multi-stage timed release of the drug in the sustained-release layer can effectively cooperate with the metabolism of the drug in the human body and maintain a stable blood drug concentration.

[0127] II. Pharmacokinetic test

[0128] Ethics Committee approved, 20 healthy subjects were selected for pharmacokinetic study. All subjects signed informed consent. Inclusion criteria: age 20-40 years, 10 women and 10 men, body weight not less than 50 kg for men and not less than 45 kg for women, no history of drug allergy, no abnormal liver and kidney metabolism. Experimental scheme, male and female were divided into two groups, one group took the reference preparation of comparative example 4 200mg / tablet, and the other group took the acyclovir tablets prepared in example 3 (200mg / tablet). Sampling time points were 10min, 20min, 30min, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 24h. LC-MS detection recorded the drug concentration in the body of the subjects, and the results are shown in the attached drawings Figure 3 .

[0129] As can be seen from Figure 3 , the sustained-release acyclovir tablets prepared in example 3 can rapidly release drugs within half an hour and increase the blood drug concentration, and through multi-stage drug release function, continuously release drugs to maintain stable blood drug concentration; compared with the commercially available reference preparation of comparative example 4, example 3 can more quickly increase the blood drug concentration, effectively reduce the maximum value of the blood drug concentration, and maintain the stable blood drug concentration for 11-12h.

[0130] Finally, it should be noted that the above examples are only used to illustrate the technical solutions of the present application and do not limit the protection scope of the present application. Although the present application has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present application can be modified or replaced by equivalents without departing from the essence and scope of the technical solutions of the present application.

Claims

1. A sustained-release acyclovir tablet, comprising, by weight: Immediate-release layer and sustained-release layer; A: Immediate-release layer Main drug: Acyclovir 130-300 doses Diluent: 100-200 parts Disintegrant: 10-30 parts of low-substituted hydroxypropyl cellulose Adhesive: 5-20 parts of crosslinked polyvinyl chloride Lubricant: 1-5 parts; Preparation of immediate-release layer particles: A1: Place the active ingredient, diluent, and disintegrant in a pulverizer and sieve through a 100-mesh screen; add an aqueous binder solution and mix to form a soft mass, then granulate through an 18-mesh screen. A2: The wet granules are fed into the dryer to bring the moisture content of the dry granules to the specified range of 2%; the dried granules are then sized using an 18-mesh sieve. A3: Add the granulated particles to the lubricant and mix them evenly to obtain the quick-release layer particles; B: Sustained-release layer Main drug: Acyclovir 150-300 doses Sustained-release matrix: Hydroxypropyl methylcellulose K100M 100-200 parts Adhesive: 10-25 parts of hydroxypropyl methylcellulose E6LV Lubricant: 3-5 parts magnesium stearate Enteric-coated membrane: Eutech S100 30-50 parts Film-forming regulator: 3-5 parts sodium ethylenediaminetetraacetate Plasticizer: Triethyl citrate (TEC) 2-5 parts; Preparation of the sustained-release layer: B1: Add the active ingredient and sustained-release matrix to a pulverizer and pulverize and mix them, then sieve through a 100-mesh sieve; add an aqueous binder solution and mix to form a soft material, then add the soft material to an extruder and rounding machine with an extrusion orifice diameter of 0.6 mm and an extrusion speed of 30 rpm, and dry it into sustained-release granules with a moisture content of 2% 1. B2: Preparation of enteric coating: The prescribed amount of enteric material was prepared into an enteric coating solution using 95% ethanol. The fluidized bed inlet air temperature was set to 35℃, the temperature of sustained-release granules 1 was controlled at 35℃, and the appropriate parameters were adjusted to control the coating weight gain by 4% to prepare sustained-release granules 2; the coating weight gain was controlled at 8% to prepare sustained-release granules 3. B3: Mix the slow-release particles 1, 2, and 3 in a weight ratio of 2:1.5:1.5, add the lubricant magnesium stearate, and obtain a slow-release layer mixed slow-release particles; C: Tableting The immediate-release granules and the sustained-release granules are mixed and pressed into a double-layer tablet with an immediate-release layer and a sustained-release layer at a weight ratio of 2:

5.

2. The sustained-release acyclovir tablet as described in claim 1, characterized in that, The diluent for the immediate-release layer is selected from at least one of sucrose, starch, lactose, and microcrystalline cellulose.

3. The sustained-release acyclovir tablet as described in claim 1, characterized in that, The lubricant for the quick-release layer is selected from at least one of magnesium stearate, micronized silica gel, and talc.

4. A preparation process for a sustained-release acyclovir tablet as described in any one of claims 1-3, characterized in that: A: Preparation of immediate-release layer particles A1: Place the active ingredient, diluent, and disintegrant in a pulverizer and sieve through a 100-mesh screen; add an aqueous binder solution and mix to form a soft mass, then granulate through an 18-mesh screen. A2: The wet granules are fed into the dryer to bring the moisture content of the dry granules to the specified range of 2%; the dried granules are then sized using an 18-mesh sieve. A3: Add the granulated particles to the lubricant and mix them evenly to obtain the quick-release layer particles; B: Preparation of the sustained-release layer B1: Add the active ingredient and sustained-release matrix to a pulverizer and pulverize and mix them, then sieve through a 100-mesh sieve; add an aqueous binder solution and mix to form a soft material, then add the soft material to an extruder and rounding machine with an extrusion orifice diameter of 0.6 mm and an extrusion speed of 30 rpm, and dry it into sustained-release granules with a moisture content of 2% 1. B2: Preparation of enteric coating: The prescribed amount of enteric material was prepared into an enteric coating solution using 95% ethanol. The fluidized bed inlet air temperature was set to 35℃, the temperature of sustained-release granules 1 was controlled at 35℃, and the appropriate parameters were adjusted to control the coating weight gain by 4% to prepare sustained-release granules 2; the coating weight gain was controlled at 8% to prepare sustained-release granules 3. B3: Mix the slow-release particles 1, 2, and 3 in a weight ratio of 2:1.5:1.5, add the lubricant magnesium stearate, and obtain a slow-release layer mixed slow-release particles; C: Tableting The immediate-release granules and the sustained-release granules are mixed and pressed into a double-layer tablet with an immediate-release layer and a sustained-release layer at a weight ratio of 2:

5.

5. Use of the sustained-release acyclovir tablets as described in any one of claims 1-3 or the sustained-release acyclovir tablets prepared by the preparation process described in claim 4 in the preparation of a medicament for treating herpes virus infection.

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