Preparation method of sustained-release famciclovir tablet for treating feline herpesvirus infection

Abstract

The invention belongs to the field of medicine preparation, and particularly relates to a preparation method of a sustained-release famciclovir tablet for treating feline herpes virus infection, the preparation method is used for preparing the sustained-release famciclovir tablet, and the preparation method comprises the following steps: preparation of quick-release layer particles, preparation of sustained-release layer particles, double-layer tabletting and coating. Three-stage drug release is realized by preparing the double-layer tablet core containing the quick release layer and the slow release layer and combining the pH responsive coating layer. The quick-release layer and the slow-release layer are granulated by adopting specific auxiliary materials according to a certain ratio, and are subjected to fluidized bed coating by using a coating solution containing hydroxypropyl methylcellulose acetate succinate after double-layer tabletting. The prepared sustained-release tablet is not released or is released in a small amount in the stomach, is continuously released in the small intestine and maintains drug release in the colon for 12 hours, the in-vitro release degree conforms to an ideal curve, the blood concentration can be maintained for a long time, meanwhile, in-vivo drug conversion supersaturation caused by excessive drug release in a short time is avoided, and the drug utilization efficiency is improved.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine preparation, in particular to a preparation method of sustained-release famciclovir tablets for treating feline herpesvirus infection. BACKGROUND

[0002] Famciclovir, as a highly effective antiviral drug, is converted into penciclovir in vivo, which inhibits herpes simplex virus DNA polymerase and shows good therapeutic effect on diseases such as herpes simplex virus and varicella-zoster virus infection. However, the traditional famciclovir ordinary tablets have the disadvantages of rapid drug release and short half-life, which requires patients to take medicine multiple times a day. This not only seriously affects the patient's medication compliance, but also causes the blood drug concentration to fluctuate greatly, resulting in "peak-trough effect", which increases the risk of adverse reactions and reduces the therapeutic effect.

[0003] To overcome the defects of traditional famciclovir ordinary tablets, the existing technology often uses a single matrix material to prepare famciclovir sustained-release tablets, trying to achieve drug release by adjusting the amount of matrix material. However, the single matrix system has significant shortcomings: on the one hand, the drug release process is easily affected by gastrointestinal peristalsis and pH environment changes, making it difficult to accurately control the drug release rate; on the other hand, it cannot meet the dual needs of rapid onset and long-term maintenance of the drug, and it is easy to cause drug burst release in the early stage, resulting in high blood drug concentration, and it is difficult to maintain effective therapeutic concentration in the later stage. In addition, although some existing sustained-release technologies improve the drug release characteristics to some extent, they have the problems of complex process, high cost, and great difficulty in industrial production, which greatly limits their wide application in clinical practice.

[0004] In the field of animal medicine, especially in the treatment of feline diseases, the application of famciclovir also faces many challenges. Cats have relatively poor ability to absorb famciclovir orally, and there are significant individual differences, mainly due to the extremely low activity of cat liver aldehyde oxidase, which leads to insufficient conversion of famciclovir to penciclovir. Related studies have shown that the pharmacokinetic characteristics of different doses of famciclovir in cats are complex, such as the oral dose and the maximum concentration (Cmax) of penciclovir in plasma are not in a simple linear relationship, and the absolute bioavailability decreases with increasing dose. At the same time, the study also shows that there are differences in the concentration of famciclovir and its metabolites in different tissues, which all bring difficulties to the effective treatment of feline herpesvirus infection.

[0005] Therefore, the present application provides a preparation method of sustained-release famciclovir tablets for treating feline herpesvirus infection. SUMMARY

[0006] In order to make up for the shortcomings of the prior art and solve at least one technical problem raised in the background art.

[0007] The technical scheme adopted by the present application to solve its technical problems is: a preparation method of a sustained-release famciclovir tablet for treating feline herpesvirus infection, which is used for preparing a sustained-release famciclovir tablet, and the preparation method comprises the following steps: S1, rapid-release layer particle preparation: mixing famciclovir, microcrystalline cellulose and cross-linked polyvinylpyrrolidone, preparing soft material with 10% PVP (K30) ethanol solution, granulating through a 20-mesh sieve, and integrating the particles after drying at 60 DEG C for 2 hours; S2, slow-release layer particle preparation: mixing famciclovir, HPMC (K15M), ethyl cellulose and PEG6000, preparing soft material with 8% HPC aqueous solution, granulating through an 18-mesh sieve, and integrating the particles after drying at 55 DEG C for 3 hours; S3, double-layer tabletting: filling the rapid-release layer particles into the bottom layer of the mold for pre-pressing, then adding the slow-release layer particles for secondary tabletting, and the total tabletting pressure is 7-9 kN; S4, pH-responsive coating: preparing an ethanol solution containing 15% HPMCAS-LF, 3% triethyl citrate and 2% talc, and using fluidized bed coating technology to coat the tablet core, with a coating weight gain of 4%, and aging at 40 DEG C for 4 hours after coating.

[0008] Preferably, the sustained-release famciclovir tablet is composed of a double-layer tablet core and a pH-responsive coating layer; The double-layer tablet core comprises a rapid-release layer and a slow-release layer, wherein the rapid-release layer accounts for 40%-50% of the total weight of the tablet core, and the slow-release layer accounts for 50%-60%; The rapid-release layer comprises 100-150 mg of famciclovir, 20-40 mg of microcrystalline cellulose and 3-8 mg of cross-linked polyvinylpyrrolidone; The slow-release layer comprises 150-200 mg of famciclovir, 70-90 mg of hydroxypropyl methyl cellulose (HPMC (K15M)), 15-25 mg of ethyl cellulose (EC) and 5-15 mg of polyethylene glycol (PEG6000); The pH-responsive coating layer accounts for 3%-6% of the total weight of the tablet, and comprises hydroxypropyl methyl cellulose acetate succinate (HPMCAS-LF), triethyl citrate and talc, and the weight ratio of HPMCAS-LF to triethyl citrate is 5:1.

[0009] Preferably, the sustained-release famciclovir tablet presents a three-stage release characteristic in the in-vitro release rate test: In a pH 1.2 hydrochloric acid solution, the cumulative release amount is ≤10% in 1 hour; In a pH 6.8 phosphate buffer, the cumulative release amount is 40%-60% in 4 hours; In a pH 7.4 phosphate buffer, the cumulative release amount is ≥85% in 12 hours.

[0010] Preferably, the microcrystalline cellulose in the immediate-release layer is of type PH102, and the cross-linked polyvinyl ketone is of type XL-10.

[0011] Preferably, the weight ratio of HPMC (K15M) to ethyl cellulose in the sustained-release layer is 4:1.

[0012] Preferably, in step S3, the pre-compression pressure is 1.5-2.5 kN and the secondary compression pressure is 7.5-8.5 kN.

[0013] Preferably, in step S4, the inlet air temperature of the fluidized bed coating is 43-47℃, and the spraying speed is 4-10g / min.

[0014] The beneficial effects of this invention are as follows: 1. The present invention discloses a method for preparing sustained-release famciclovir tablets for treating feline herpesvirus infection. This preparation method achieves three-stage drug release through the synergistic design of a double-layer core structure and a pH-responsive coating layer. In the acidic environment of the stomach (pH 1.2), the coating layer does not dissolve, and only the immediate-release layer releases no drug or a small amount of drug, avoiding premature and excessive drug release and preventing drug degradation in an acidic environment. Upon entering the small intestine (pH 6.8), the coating dissolves, and the immediate-release layer releases a large amount of drug, rapidly reaching the required therapeutic blood drug concentration, while the sustained-release layer begins to slowly release the drug. In the colon (pH 7.4), the matrix further dissolves, continuously releasing the drug for up to 12 hours, maintaining blood drug concentration, while avoiding the reduction in in vivo conversion efficiency caused by excessive drug release in a short period, thus improving drug utilization efficiency, prolonging the duration of drug action, reducing the dosage and frequency of administration, and improving medication adherence.

[0015] 2. The present invention discloses a method for preparing sustained-release famciclovir tablets for treating feline herpesvirus infection. The sustained-release layer uses a composite matrix material of HPMC (K15M) and ethyl cellulose (EC), combined with PEG6000 as a porogen, to form a synergistic controlled-release network. HPMC (K15M) swells upon contact with water to form a gel layer, while EC slowly dissolves. Both work together to regulate the drug release rate. Compared with a single matrix material, this method can more precisely control the drug release curve, ensuring stable and continuous drug release in vivo and improving the therapeutic effect.

[0016] 3. The present invention describes a method for preparing sustained-release famciclovir tablets for treating feline herpesvirus infection. During the granulation process, different binders and process parameters are selected for the immediate-release and sustained-release layers. The immediate-release layer is granulated using a 10% PVPK30 ethanol solution. Ethanol's high volatility allows for rapid drying, reducing the risk of drug degradation in humid and hot environments. Simultaneously, the good hydrophilicity of PVPK30 facilitates rapid disintegration of the immediate-release particles, enabling rapid drug onset of action. The sustained-release layer is granulated using an 8% HPC aqueous solution. Combined with specific drying temperatures and times, this ensures complete curing of the EC (extracorporeal membrane oxygenation), giving the sustained-release particles suitable mechanical strength and drug release performance. Furthermore, precise control of pre-compression and secondary compression pressures in the double-layer tableting process, along with parameters such as inlet air temperature and spray speed set using fluidized bed coating technology, ensures tablet hardness, appearance quality, and coating uniformity, improving product quality stability.

[0017] 4. The present invention discloses a method for preparing sustained-release famciclovir tablets for treating feline herpesvirus infection. The prepared sustained-release famciclovir tablets exhibit ideal three-stage release characteristics in in vitro release tests: ≤10% cumulative release in pH 1.2 hydrochloric acid solution after 1 hour, 40%-60% cumulative release in pH 6.8 phosphate buffer after 4 hours, and ≥85% cumulative release in pH 7.4 phosphate buffer after 12 hours. Compared with existing technologies, this method better simulates the gastrointestinal environment, making drug release more consistent with the physiological characteristics of cats, which helps to improve drug utilization, maintain stable blood drug concentration, and enhance therapeutic effects.

[0018] 5. The method for preparing sustained-release famciclovir tablets for treating feline herpesvirus infection described in this invention, verified through accelerated and long-term experiments, shows that the sustained-release famciclovir tablets prepared by this method exhibit a content variation of ≤5% and a release curve f2 ≥ 50, indicating that the drug has good stability under different storage conditions, the active ingredient is not easily degraded, and the drug release performance is stable. Furthermore, this preparation method is suitable for industrial production; the equipment and process parameters used are easy to control and highly reproducible, providing a reliable guarantee for the large-scale production and clinical application of the product. Detailed Implementation

[0019] To make the technical means, creative features, objectives and effects of this invention easier to understand, the invention will be further described below in conjunction with specific embodiments.

[0020] This invention discloses a method for preparing sustained-release famciclovir tablets for treating feline herpesvirus infection. The method comprises the following steps: S1. Preparation of immediate-release layer particles: Famciclovir, microcrystalline cellulose and cross-linked polyvinylpyrrolidone are mixed, and a soft material is prepared by using a 10% PVP (K30) ethanol solution. The material is then granulated by passing it through a 20-mesh sieve and dried at 60°C for 2 hours before being granulated. S2. Preparation of sustained-release layer particles: Famciclovir, HPMC (K15M), ethyl cellulose and PEG6000 are mixed, and a soft material is prepared with 8% HPC aqueous solution. The mixture is then granulated by passing it through an 18-mesh sieve and dried at 55°C for 3 hours before being granulated. S3, Double-layer tableting: First, the immediate-release layer particles are filled into the bottom layer of the mold for pre-compression, and then the sustained-release layer particles are added for secondary tableting. The total tableting pressure is 7-9kN. S4, pH-responsive coating: Prepare an ethanol solution containing 15% HPMCAS-LF, 3% triethyl citrate and 2% talc, and use fluidized bed coating technology to coat the tablet cores. The coating weight gain is 4%, and the tablets are aged at 40°C for 4 hours after coating.

[0021] Sustained-release famciclovir tablets consist of a double-layer tablet core and a pH-responsive coating layer; The dual-layer tablet core consists of an immediate-release layer and a sustained-release layer, with the immediate-release layer accounting for 40%-50% of the total weight of the tablet core and the sustained-release layer accounting for 50%-60%. The immediate-release layer contains 100-150 mg famciclovir, 20-40 mg microcrystalline cellulose, and 3-8 mg crospovidone; The sustained-release layer contains 150-200 mg famciclovir, 70-90 mg hydroxypropyl methylcellulose (HPMC (K15M)), 15-25 mg ethyl cellulose (EC) and 5-15 mg polyethylene glycol (PEG6000). The pH-responsive coating layer comprises 3%-6% of the total tablet weight and includes hydroxypropyl methylcellulose acetate succinate (HPMCAS-LF), triethyl citrate, and talc, with a weight ratio of HPMCAS-LF to triethyl citrate of 5:1.

[0022] Sustained-release famciclovir tablets exhibited a three-stage release profile in in vitro release tests: In a hydrochloric acid solution with pH 1.2, the cumulative release over 1 hour is ≤10%. In pH 6.8 phosphate buffer, the cumulative release over 4 hours was 40%-60%; In pH 7.4 phosphate buffer, the cumulative release over 12 hours is ≥85%.

[0023] The microcrystalline cellulose in the immediate-release layer is of type PH102, and the cross-linked polyvinyl ketone is of type XL-10.

[0024] The weight ratio of HPMC (K15M) to ethyl cellulose in the sustained-release layer is 4:1.

[0025] In step S3, the pre-compression pressure is 1.5-2.5kN, and the secondary compression pressure is 7.5-8.5kN.

[0026] In step S4, the inlet air temperature for fluidized bed coating is 43-47℃, and the spraying speed is 4-10g / min.

[0027] Specifically, I. Preparation of Immediate-Release Layer Particles Famciclovir (100mg), microcrystalline cellulose (30mg), and crospovidone (5mg) were passed through a 60-mesh sieve and mixed for 15 minutes.

[0028] Add 10% PVPK30 ethanol solution to prepare a soft material, and then granulate it through a 20-mesh sieve.

[0029] Dry at 60℃ for 2 hours, then granulate (through an 18-mesh sieve).

[0030] II. Preparation of sustained-release layer particles Pass famciclovir (150mg), HPMC (K15M) (80mg), ethyl cellulose (20mg), and PEG6000 (10mg) through a 60-mesh sieve and mix for 20 minutes.

[0031] Add 8% HPC aqueous solution to prepare a soft material, and granulate it through an 18-mesh sieve.

[0032] Dry at 55℃ for 3 hours (to ensure EC is fully cured), then granulate (16 mesh sieve).

[0033] III. Double-layer tableting Fill the bottom layer of the mold with the quick-release granules and pre-press (pressure 2kN).

[0034] Add sustained-release particles and compress the tablets twice (total pressure 8kN) to obtain a double-layer tablet core (diameter 8mm, hardness 4-5kg).

[0035] IV. pH-responsive coating Preparation of coating solution: HPMCAS-LF (15mg) + triethyl citrate (3mg) + talc (2mg) are dissolved in 80% ethanol solution (solid content 10%).

[0036] Fluidized bed coating technology was used, with the following control conditions: Inlet air temperature: 45±2℃ Spraying speed: 5-8 g / min Weight gain from coating: 4% (w / w) After coating, age at 40°C for 4 hours to fully cure the film material.

[0037] Furthermore, Drug release mechanism: A bilayer framework + pH-responsive coating enables three-stage release. (1) In the stomach (pH 1.2): the coating is insoluble, and the immediate-release layer is not released or is released in small amounts (≤10% within 1 hour). (2) Small intestine (pH 6.8): The coating dissolves and the sustained-release layer begins to release (40%-60% released in 4 hours); (3) Colon (pH 7.4): The skeleton is further dissolved, and the release continues for up to 12 hours.

[0038] Excipient combination: HPMC+EC composite framework, synergistic controlled release.

[0039] Coating design: pH-responsive HPMCAS-LF coating to prevent drug release into the stomach.

[0040] Drug distribution: immediate-release layer (40% dose) + sustained-release layer (60% dose).

[0041] In vitro release curves: 1h: ≤10%; 4h: 40%-60%; 12h: ≥85%.

[0042] Furthermore, I. Release Rate Test Medium: pH 1.2 hydrochloric acid solution (0-2h) - pH 6.8 phosphate buffer (2-12h).

[0043] Method: Paddle method, 50 rpm, 37℃.

[0044] Standard: Meets the three-stage release characteristics (see above).

[0045] II. Stability Testing Accelerated test (40℃ / 75%RH, 6 months): content change ≤2%, release curve f2≥50.

[0046] Long-term test (25℃ / 60%RH, 24 months): content change ≤2%, release curve f2≥50.

[0047] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the present invention as claimed. The scope of protection of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing sustained-release famciclovir tablets for treating feline herpesvirus infection, characterized in that, It is used to prepare sustained-release famciclovir tablets, and the preparation method includes the following steps: S1. Preparation of immediate-release layer particles: Famciclovir, microcrystalline cellulose and cross-linked polyvinylpyrrolidone are mixed, and a soft material is prepared by using a 10% PVP (K30) ethanol solution. The material is then granulated by passing it through a 20-mesh sieve and dried at 60°C for 2 hours before being granulated. S2. Preparation of sustained-release layer particles: Famciclovir, HPMC (K15M), ethyl cellulose and PEG6000 are mixed, and a soft material is prepared with 8% HPC aqueous solution. The mixture is then granulated by passing it through an 18-mesh sieve and dried at 55°C for 3 hours before being granulated. S3, Double-layer tableting: First, the immediate-release layer particles are filled into the bottom layer of the mold for pre-compression, and then the sustained-release layer particles are added for secondary tableting. The total tableting pressure is 7-9kN. S4, pH-responsive coating: Prepare an ethanol solution containing 15% HPMCAS-LF, 3% triethyl citrate and 2% talc, and use fluidized bed coating technology to coat the tablet cores. The coating weight gain is 4%, and the tablets are aged at 40°C for 4 hours after coating.

2. The method for preparing sustained-release famciclovir tablets for treating feline herpesvirus infection according to claim 1, characterized in that: The sustained-release famciclovir tablets consist of a double-layer tablet core and a pH-responsive coating layer; The dual-layer tablet core comprises an immediate-release layer and a sustained-release layer, wherein the immediate-release layer accounts for 40%-50% of the total weight of the tablet core, and the sustained-release layer accounts for 50%-60%. The immediate-release layer contains 100-150 mg famciclovir, 20-40 mg microcrystalline cellulose and 3-8 mg crospovidone; The sustained-release layer contains 150-200 mg famciclovir, 70-90 mg hydroxypropyl methylcellulose, 15-25 mg ethylcellulose, and 5-15 mg polyethylene glycol; The pH-responsive coating layer comprises 3%-6% of the total weight of the tablet and includes hydroxypropyl methylcellulose acetate succinate, triethyl citrate, and talc, with a weight ratio of HPMCAS-LF to triethyl citrate of 5:

1.

3. The method for preparing sustained-release famciclovir tablets for treating feline herpesvirus infection according to claim 1, characterized in that: The sustained-release famciclovir tablets exhibited a three-stage release characteristic in in vitro release tests: In a hydrochloric acid solution with pH 1.2, the cumulative release over 1 hour is ≤10%. In pH 6.8 phosphate buffer, the cumulative release over 4 hours was 40%-60%; In pH 7.4 phosphate buffer, the cumulative release over 12 hours is ≥85%.

4. The method for preparing sustained-release famciclovir tablets for treating feline herpesvirus infection according to claim 1, characterized in that: The microcrystalline cellulose in the immediate-release layer is of type PH102, and the cross-linked polyvinyl ketone is of type XL-10.

5. The method for preparing sustained-release famciclovir tablets for treating feline herpesvirus infection according to claim 1, characterized in that: The weight ratio of HPMC (K15M) to ethyl cellulose in the sustained-release layer is 4:

1.

6. The method for preparing sustained-release famciclovir tablets for treating feline herpesvirus infection according to claim 1, characterized in that: In step S3, the pre-compression pressure is 1.5-2.5 kN, and the secondary compression pressure is 7.5-8.5 kN.

7. The method for preparing sustained-release famciclovir tablets for treating feline herpesvirus infection according to claim 1, characterized in that: In step S4, the inlet air temperature of the fluidized bed coating is 43-47℃, and the spraying speed is 4-10g / min.