CN112168791B - Valacyclovir hydrochloride liposome tablet and preparation method thereof - Google Patents
Valacyclovir hydrochloride liposome tablet and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a valacyclovir hydrochloride liposome tablet, which comprises a valacyclovir hydrochloride liposome, a filler, an excipient, a disintegrating agent, an adhesive and a lubricant, wherein the valacyclovir hydrochloride liposome consists of valacyclovir hydrochloride, cholesterol, soybean lecithin and polyvinylpyrrolidone-K30; the preparation method of the valacyclovir hydrochloride liposome tablet comprises the following steps: (1) preparation of valacyclovir hydrochloride liposome, (2) mixing, and (3) tabletting. The valacyclovir hydrochloride liposome tablet with good stability, excellent disintegration property and high bioavailability is obtained by adopting specific auxiliary materials and selecting a proper proportion; the valacyclovir hydrochloride liposome tablet of the invention not only has far higher stability and bioavailability than the products in the prior art, but also brings great convenience for clinical medication.
Description
Technical Field
The invention relates to the technical field of medicine science and technology, in particular to preparation and application of valacyclovir hydrochloride liposome tablets.
Background
Valacyclovir Hydrochloride is L-valine-2- [ (6-oxo-2-amino-1, 6-dihydro-9H-purin-9-yl) methoxy ] ethyl ester Hydrochloride, known as Valaciclovir Hydrochloride.
Valacyclovir hydrochloride is a prodrug of Acyclovir (ACV), is absorbed quickly after being taken orally and is converted into acyclovir quickly in vivo, the antiviral effect of the valacyclovir hydrochloride is caused by the effect of parent acyclovir, and the valacyclovir hydrochloride is open-chain purine nucleoside, can inhibit the synthesis of virus deoxyribonucleic acid and has little effect on the synthesis of host cell DNA. After acyclovir enters herpes infected cells, it competes with deoxynucleosides for viral thymidine kinase or cellular kinase, the drug is phosphorylated to active acyclovir triphosphate, which acts as a substrate for viral DNA replication and competes with deoxyguanine triphosphate for viral DNA polymerase, thereby inhibiting viral DNA synthesis and exhibiting antiviral efficacy. The product has high curative effect on herpes simplex virus I and II and varicella zoster virus, and has low toxicity to host cell of mammal.
The oral bioavailability of the product is 3-5 times of that of ACV, the defect that the ACV is inconvenient to take (orally taken 5 times a day) is overcome, only 2 times a day are needed, the oral administration of a certain dosage of the product is similar to the pharmacokinetic parameters of intravenous ACV, therefore, the clinical use of the product is more convenient, the compliance of patients is better, the in vivo antiviral activity of the product is superior to that of acyclovir, and the treatment indexes of herpes simplex virus I and II are respectively 42.91 percent and 30.13 percent higher than that of acyclovir. However, valacyclovir hydrochloride is easy to degrade to generate acyclovir during storage, and the prior art does not mention how to solve the problem; in addition, the prior art does not provide a corresponding technical scheme for improving the disintegration and the dissolution of valacyclovir hydrochloride.
CN103462918A discloses an antiviral valacyclovir hydrochloride tablet, which contains sodium bicarbonate as an effervescent agent to rapidly dissolve the drug. However, the addition of alkaline substance is more unfavorable for the stability of acidic valacyclovir hydrochloride.
Disclosure of Invention
In order to partially solve the technical problems, the invention provides a valacyclovir hydrochloride liposome tablet and a preparation method thereof, and the specific technical scheme is as follows: a valacyclovir hydrochloride liposome tablet comprises valacyclovir hydrochloride liposome, a filler, an excipient, a disintegrating agent, an adhesive and a lubricant, wherein the valacyclovir hydrochloride liposome comprises 1 part of valacyclovir hydrochloride liposome, 5-6 parts of the filler, 0.1-0.3 part of the excipient, 2-5 parts of the disintegrating agent, 2-5 parts of the adhesive and 0.5-1 part of the lubricant in parts by weight; the valacyclovir hydrochloride liposome consists of valacyclovir hydrochloride, cholesterol, soybean lecithin and polyvinylpyrrolidone-K30, wherein the weight ratio of the valacyclovir hydrochloride to the cholesterol to the soybean lecithin to the polyvinylpyrrolidone-K30 is 1:1-3:5-10: 6-8.
The filler is microcrystalline cellulose.
The excipient is sodium chloride powder.
The disintegrating agent is one of croscarmellose sodium or chitin.
The adhesive is polyvinylpyrrolidone/vinyl acetate copolymer.
The lubricant is one or more of magnesium stearate, micropowder silica gel and sodium stearyl fumarate.
In some embodiments, the valacyclovir hydrochloride liposome tablet preferably comprises 1 part of valacyclovir hydrochloride liposome, 6 parts of microcrystalline cellulose, 0.3 part of sodium chloride powder, 2 parts of chitin, 4.4 parts of polyvinylpyrrolidone/vinyl acetate copolymer and 0.8 part of magnesium stearate; the valacyclovir hydrochloride liposome is prepared from valacyclovir hydrochloride, cholesterol, soybean lecithin and polyvinylpyrrolidone-K30 in a weight ratio of 1:1:8: 6.
A preparation method of valacyclovir hydrochloride liposome tablets comprises the following steps: (1) preparation of valacyclovir hydrochloride liposome: weighing valacyclovir hydrochloride, cholesterol and soybean lecithin in a certain proportion, dissolving the valacyclovir hydrochloride, the cholesterol and the soybean lecithin in a solvent, removing the solvent on a rotary evaporator at 60 ℃ under a vacuum condition to obtain a film, and continuously evaporating for 2 hours to completely remove all trace solvents and obtain a dry film; hydrating the dry film with a suitable amount of phosphate buffer containing polyvinylpyrrolidone-K30 at 45 deg.C for 15min to obtain a liposome solution; sonicating the obtained liposome for 5 minutes to obtain small and uniform vesicles, and freeze-drying the obtained dry liposome powder and storing at 4 ℃ until use; (2) mixing: adding a proper amount of ethanol into the liposome powder, the filler, the adhesive and the disintegrating agent in the step (1) to prepare a soft material, sieving the soft material with a 24-mesh sieve for granulation, drying the soft material at 55 ℃, and finishing granules of 16 meshes to prepare valacyclovir hydrochloride liposome particles; (3) tabletting: and (3) uniformly mixing the valacyclovir hydrochloride lipidosome particles obtained in the step (2), the excipient and the lubricant in a three-way motion mixer according to an equivalent progressive method, controlling the weight of the tablets, and tabletting to obtain the valacyclovir hydrochloride lipidosome tablets.
The solvent in the step (1) is a mixed solution of dichloromethane and methanol in a volume ratio of 3: 1.
Compared with the prior art, the invention has the following advantages:
1. the valacyclovir hydrochloride liposome has high entrapment rate, and the entrapment rate exceeds 80%; the polyvinylpyrrolidone-K30 is an amphiphilic polymer, and can improve the stability of the liposome and smoothen the outer layer of the liposome when being used with the liposome, thereby protecting the liposome from adhesion and aggregation in the gastrointestinal tract environment and being a good protective agent for the liposome;
2. when the valacyclovir hydrochloride liposome tablet is in an aqueous medium, the polyvinylpyrrolidone/vinyl acetate copolymer can be dissolved into nearby water, so that higher local polymer concentration is generated on the surface of the tablet, higher local viscosity is caused, and the disintegration of the tablet is influenced; the neutral inorganic salt sodium chloride changes the solubility of the polymer by ionic water interaction, the homogeneous salt sodium chloride tends to bind with water and form a more ordered water structure, and the ions with higher surface charge density are more competitive with water molecules, thus more effectively salting out the polymer, reducing the gelling of the polymer and the formation of sticky layers on the tablet surface, and thus achieving the disintegration of the tablet. I.e. sodium chloride depresses the cloud point of the polymer and slows its dissolution, thus delaying the formation of the viscous layer and allowing time for disintegration;
3. the chitin is added as a disintegrating agent, the chitin is not influenced by other excipients or additives, and the chitin shows good performance compared with other disintegrating agents, and the obtained tablet has good disintegrating performance and good tabletting performance;
4. the valacyclovir hydrochloride liposome tablet with good stability, excellent disintegration property and high bioavailability is obtained by adopting specific auxiliary materials and selecting a proper proportion;
5. the valacyclovir hydrochloride liposome tablet of the invention not only has far higher stability and bioavailability than the products in the prior art, but also brings great convenience for clinical medication.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1:
a preparation method of valacyclovir hydrochloride liposome tablets comprises the following steps:
(1) preparation of valacyclovir hydrochloride liposome: weighing 1g of valacyclovir hydrochloride, 1g of cholesterol and 8g of soybean lecithin, dissolving the valacyclovir hydrochloride, the cholesterol and the soybean lecithin in a mixed solution of dichloromethane and methanol in a volume ratio of 3:1, removing the solvent on a rotary evaporator at 60 ℃ under a vacuum condition to obtain a film, and continuously evaporating for 2 hours to completely remove all trace solvents and obtain a dry film; hydrating the dry film with an appropriate amount of 20mL phosphate buffer solution containing 6g polyvinylpyrrolidone-K30 at 45 deg.C for 15 minutes to obtain a liposome solution; subjecting the obtained liposome to ultrasonic treatment for 5min to obtain small and uniform vesicle, freeze-drying, sieving the obtained dried liposome powder with 80 mesh sieve, and storing at 4 deg.C until use;
(2) mixing: adding a proper amount of ethanol into 1g of liposome powder, 5g of microcrystalline cellulose, 3g of polyvinylpyrrolidone/vinyl acetate copolymer and 5g of croscarmellose sodium in the step (1) to prepare a soft material, sieving the soft material with a 24-mesh sieve for granulation, drying at 55 ℃, and grading by 16 meshes to prepare valacyclovir hydrochloride liposome particles;
(3) tabletting: and (3) uniformly mixing the valacyclovir hydrochloride liposome particles obtained in the step (2) and 0.5g of magnesium stearate in a three-way motion mixer by an equivalent progressive addition method, controlling the weight of the tablets, and tabletting to obtain the valacyclovir hydrochloride liposome tablets.
Example 2:
a preparation method of valacyclovir hydrochloride liposome tablets comprises the following steps:
(1) preparation of valacyclovir hydrochloride liposome: weighing 1g of valacyclovir hydrochloride, 1g of cholesterol and 8g of soybean lecithin, dissolving the valacyclovir hydrochloride, the cholesterol and the soybean lecithin in a mixed solution of dichloromethane and methanol in a volume ratio of 3:1, removing the solvent on a rotary evaporator at 60 ℃ under a vacuum condition to obtain a film, and continuously evaporating for 2 hours to completely remove all trace solvents and obtain a dry film; hydrating the dry film with an appropriate amount of 20mL phosphate buffer solution containing 6g polyvinylpyrrolidone-K30 at 45 deg.C for 15 minutes to obtain a liposome solution; subjecting the obtained liposome to ultrasonic treatment for 5min to obtain small and uniform vesicle, freeze-drying, sieving the obtained dried liposome powder with 80 mesh sieve, and storing at 4 deg.C until use;
(2) mixing: adding a proper amount of ethanol into 1g of liposome powder, 5g of microcrystalline cellulose, 3g of polyvinylpyrrolidone/vinyl acetate copolymer and 5g of chitin in the step (1) to prepare a soft material, sieving the soft material with a 24-mesh sieve for granulation, drying at 55 ℃, and finishing granules of 16 meshes to prepare valacyclovir hydrochloride liposome particles;
(3) tabletting: and (3) uniformly mixing the valacyclovir hydrochloride liposome particles obtained in the step (2) and 0.5g of magnesium stearate in a three-way motion mixer by an equivalent progressive method, controlling the weight of the tablets, and tabletting to obtain the valacyclovir hydrochloride liposome tablets.
Example 3:
a preparation method of valacyclovir hydrochloride liposome tablets comprises the following steps:
(1) preparation of valacyclovir hydrochloride liposome: weighing 1g of valacyclovir hydrochloride, 1g of cholesterol and 8g of soybean lecithin, dissolving the valacyclovir hydrochloride, the cholesterol and the soybean lecithin in a mixed solution of dichloromethane and methanol in a volume ratio of 3:1, removing the solvent on a rotary evaporator at 60 ℃ under a vacuum condition to obtain a film, and continuously evaporating for 2 hours to completely remove all trace solvents and obtain a dry film; hydrating the dry film with an appropriate amount of 20mL phosphate buffer solution containing 6g polyvinylpyrrolidone-K30 at 45 deg.C for 15 minutes to obtain a liposome solution; subjecting the obtained liposome to ultrasonic treatment for 5min to obtain small and uniform vesicle, freeze-drying, sieving the obtained dried liposome powder with 80 mesh sieve, and storing at 4 deg.C until use;
(2) mixing: adding a proper amount of ethanol into 1g of liposome powder, 6g of microcrystalline cellulose, 3g of polyvinylpyrrolidone/vinyl acetate copolymer and 3.9g of chitin obtained in the step (1) to prepare a soft material, sieving the soft material with a 24-mesh sieve for granulation, drying at 55 ℃, and finishing granules with 16 meshes to prepare valacyclovir hydrochloride liposome particles;
(3) tabletting: and (3) uniformly mixing the valacyclovir hydrochloride liposome particles obtained in the step (2), 0.1g of sodium chloride powder and 0.5g of magnesium stearate in a three-way motion mixer by an equivalent progressive method, controlling the weight of the tablets, and tabletting to obtain the valacyclovir hydrochloride liposome tablets.
Example 4:
a preparation method of valacyclovir hydrochloride liposome tablets comprises the following steps:
(1) preparation of valacyclovir hydrochloride liposome: weighing 1g of valacyclovir hydrochloride, 1g of cholesterol and 8g of soybean lecithin, dissolving the valacyclovir hydrochloride, the cholesterol and the soybean lecithin in a mixed solution of dichloromethane and methanol in a volume ratio of 3:1, removing the solvent on a rotary evaporator at 60 ℃ under a vacuum condition to obtain a film, and continuously evaporating for 2 hours to completely remove all trace solvents and obtain a dry film; hydrating the dry film with an appropriate amount of 20mL phosphate buffer solution containing 6g polyvinylpyrrolidone-K30 at 45 deg.C for 15 minutes to obtain a liposome solution; subjecting the obtained liposome to ultrasonic treatment for 5min to obtain small and uniform vesicle, freeze-drying, sieving the obtained dried liposome powder with 80 mesh sieve, and storing at 4 deg.C until use;
(2) mixing: adding a proper amount of ethanol into 1g of liposome powder, 6g of microcrystalline cellulose, 3g of polyvinylpyrrolidone/vinyl acetate copolymer and 3.2g of chitin obtained in the step (1) to prepare a soft material, sieving the soft material with a 24-mesh sieve for granulation, drying at 55 ℃, and finishing granules with 16 meshes to prepare valacyclovir hydrochloride liposome particles;
(3) tabletting: and (3) uniformly mixing the valacyclovir hydrochloride liposome particles obtained in the step (2), 0.3g of sodium chloride powder and 1g of magnesium stearate in a three-way motion mixer by an equivalent progressive method, controlling the weight of the tablets, and tabletting to obtain the valacyclovir hydrochloride liposome tablets.
Example 5:
a preparation method of valacyclovir hydrochloride liposome tablets comprises the following steps:
(1) preparation of valacyclovir hydrochloride liposome: weighing 1g of valacyclovir hydrochloride, 1g of cholesterol and 8g of soybean lecithin, dissolving the valacyclovir hydrochloride, the cholesterol and the soybean lecithin in a mixed solution of dichloromethane and methanol in a volume ratio of 3:1, removing the solvent on a rotary evaporator at 60 ℃ under a vacuum condition to obtain a film, and continuously evaporating for 2 hours to completely remove all trace solvents and obtain a dry film; hydrating the dry film with an appropriate amount of 20mL phosphate buffer solution containing 6g polyvinylpyrrolidone-K30 at 45 deg.C for 15 minutes to obtain a liposome solution; subjecting the obtained liposome to ultrasonic treatment for 5min to obtain small and uniform vesicle, freeze-drying, sieving the obtained dried liposome powder with 80 mesh sieve, and storing at 4 deg.C until use;
(2) mixing: adding a proper amount of ethanol into 1g of liposome powder, 6g of microcrystalline cellulose, 4.4g of polyvinylpyrrolidone/vinyl acetate copolymer and 2g of chitin obtained in the step (1) to prepare a soft material, sieving the soft material with a 24-mesh sieve for granulation, drying at 55 ℃, and finishing granules with 16 meshes to prepare valacyclovir hydrochloride liposome particles;
(3) tabletting: and (3) uniformly mixing the valacyclovir hydrochloride liposome particles obtained in the step (2), 0.3g of sodium chloride powder and 0.8g of magnesium stearate in a three-way motion mixer by an equivalent progressive method, controlling the weight of the tablets, and tabletting to obtain the valacyclovir hydrochloride liposome tablets.
Example 6:
a preparation method of valacyclovir hydrochloride liposome tablets comprises the following steps:
(1) preparation of valacyclovir hydrochloride liposome: weighing 1g of valacyclovir hydrochloride, 1g of cholesterol and 8g of soybean lecithin, dissolving the valacyclovir hydrochloride, the cholesterol and the soybean lecithin in a mixed solution of dichloromethane and methanol in a volume ratio of 3:1, removing the solvent on a rotary evaporator at 60 ℃ under a vacuum condition to obtain a film, and continuously evaporating for 2 hours to completely remove all trace solvents and obtain a dry film; hydrating the dry film with an appropriate amount of 20mL phosphate buffer solution containing 6g polyvinylpyrrolidone-K30 at 45 deg.C for 15 minutes to obtain a liposome solution; subjecting the obtained liposome to ultrasonic treatment for 5min to obtain small and uniform vesicle, freeze-drying, sieving the obtained dried liposome powder with 80 mesh sieve, and storing at 4 deg.C until use;
(2) mixing: adding a proper amount of ethanol into 1g of liposome powder, 5g of microcrystalline cellulose, 2.4g of polyvinylpyrrolidone/vinyl acetate copolymer and 5g of chitin obtained in the step (1) to prepare a soft material, sieving the soft material with a 24-mesh sieve for granulation, drying at 55 ℃, and finishing granules with 16 meshes to prepare valacyclovir hydrochloride liposome particles;
(3) tabletting: and (3) uniformly mixing the valacyclovir hydrochloride liposome particles obtained in the step (2), 0.3g of sodium chloride powder and 0.8g of magnesium stearate in a three-way motion mixer by an equivalent progressive method, controlling the weight of the tablets, and tabletting to obtain the valacyclovir hydrochloride liposome tablets.
Example 7:
a preparation method of valacyclovir hydrochloride liposome tablets comprises the following steps:
(1) preparation of valacyclovir hydrochloride liposome: weighing 1g of valacyclovir hydrochloride, 3g of cholesterol and 5g of soybean lecithin, dissolving the valacyclovir hydrochloride, the cholesterol and the soybean lecithin in a mixed solution of dichloromethane and methanol in a volume ratio of 3:1, removing the solvent on a rotary evaporator at 60 ℃ under a vacuum condition to obtain a film, and continuously evaporating for 2 hours to completely remove all trace solvents and obtain a dry film; hydrating the dry film with a suitable amount of 20mL phosphate buffer solution containing 8g polyvinylpyrrolidone-K30 at 45 deg.C for 15 minutes to obtain a liposome solution; subjecting the obtained liposome to ultrasonic treatment for 5min to obtain small and uniform vesicle, freeze-drying, sieving the obtained dried liposome powder with 80 mesh sieve, and storing at 4 deg.C until use;
(2) mixing: adding a proper amount of ethanol into 1g of liposome powder, 6g of microcrystalline cellulose, 4.4g of polyvinylpyrrolidone/vinyl acetate copolymer and 2g of chitin obtained in the step (1) to prepare a soft material, sieving the soft material with a 24-mesh sieve for granulation, drying at 55 ℃, and finishing granules with 16 meshes to prepare valacyclovir hydrochloride liposome particles;
(3) tabletting: and (3) uniformly mixing the valacyclovir hydrochloride liposome particles obtained in the step (2), 0.3g of sodium chloride powder and 0.8g of magnesium stearate in a three-way motion mixer by an equivalent progressive method, controlling the weight of the tablets, and tabletting to obtain the valacyclovir hydrochloride liposome tablets.
Example 8
A preparation method of valacyclovir hydrochloride liposome tablets comprises the following steps:
(1) preparation of valacyclovir hydrochloride liposome: weighing 1g of valacyclovir hydrochloride, 1g of cholesterol and 8g of soybean lecithin, dissolving the valacyclovir hydrochloride, the cholesterol and the soybean lecithin in a mixed solution of dichloromethane and methanol in a volume ratio of 3:1, removing the solvent on a rotary evaporator at 60 ℃ under a vacuum condition to obtain a film, and continuously evaporating for 2 hours to completely remove all trace solvents and obtain a dry film; hydrating the dry film at 45 ℃ for 15 minutes with 20mL of phosphate buffer to obtain a liposome solution; subjecting the obtained liposome to ultrasonic treatment for 5min to obtain small and uniform vesicle, freeze-drying, sieving the obtained dried liposome powder with 80 mesh sieve, and storing at 4 deg.C until use;
(2) mixing: adding a proper amount of ethanol into 1g of liposome powder, 6g of microcrystalline cellulose, 4.4g of polyvinylpyrrolidone/vinyl acetate copolymer and 2g of chitin obtained in the step (1) to prepare a soft material, sieving the soft material with a 24-mesh sieve for granulation, drying at 55 ℃, and finishing granules with 16 meshes to prepare valacyclovir hydrochloride liposome particles;
(3) tabletting: and (3) uniformly mixing the valacyclovir hydrochloride liposome particles obtained in the step (2), 0.3g of sodium chloride powder and 0.8g of magnesium stearate in a three-way motion mixer by an equivalent progressive method, controlling the weight of the tablets, and tabletting to obtain the valacyclovir hydrochloride liposome tablets.
Example 9
A preparation method of valacyclovir hydrochloride liposome tablets comprises the following steps:
(1) preparation of valacyclovir hydrochloride liposome: weighing 1g of valacyclovir hydrochloride, 1g of cholesterol and 8g of soybean lecithin, dissolving the valacyclovir hydrochloride, the cholesterol and the soybean lecithin in a mixed solution of dichloromethane and methanol in a volume ratio of 3:1, removing the solvent on a rotary evaporator at 60 ℃ under a vacuum condition to obtain a film, and continuously evaporating for 2 hours to completely remove all trace solvents and obtain a dry film; hydrating the dry film with an appropriate amount of 20mL phosphate buffer solution containing 6g polyvinylpyrrolidone-K30 at 45 deg.C for 15 minutes to obtain a liposome solution; subjecting the obtained liposome to ultrasonic treatment for 5min to obtain small and uniform vesicle, freeze-drying, sieving the obtained dried liposome powder with 80 mesh sieve, and storing at 4 deg.C until use;
(2) mixing: adding a proper amount of ethanol into 1g of liposome powder, 6g of microcrystalline cellulose, 4.4g of polyvinylpyrrolidone/vinyl acetate copolymer and 2g of chitin obtained in the step (1) to prepare a soft material, sieving the soft material with a 24-mesh sieve for granulation, drying at 55 ℃, and finishing granules with 16 meshes to prepare valacyclovir hydrochloride liposome particles;
(3) tabletting: and (3) uniformly mixing the valacyclovir hydrochloride liposome particles obtained in the step (2), 0.3g of sodium bicarbonate and 0.8g of magnesium stearate in a three-way motion mixer by an equivalent progressive method, controlling the weight of the tablets, and tabletting to obtain the valacyclovir hydrochloride liposome tablets.
Test example 1: dissolution rate
Valacyclovir hydrochloride tablets prepared in examples 1 to 8 were taken, and according to the dissolution test method (appendix XC second method), 900ml of 0.lmol/L hydrochloric acid solution was used as the dissolution medium at a rotation speed of 50 rpm, and according to the method, 10ml of the solution was taken at 15 minutes, filtered, an appropriate amount of the subsequent filtrate was taken at a precise rate, and the subsequent solution was diluted quantitatively with 0.lmol/L hydrochloric acid solution to give a solution containing about 10. mu.g per lml. Immediately determining the absorbance at a wavelength of 254nm by UV-visible spectrophotometry (appendix IVA); taking a proper amount of valacyclovir hydrochloride reference substance, precisely weighing, dissolving with 0.1mol/L hydrochloric acid solution, quantitatively diluting to obtain a solution containing about 10 μ g of valacyclovir per lml, measuring by the same method, and calculating the dissolution amount of each tablet. The limit is 80% of the indicated amount, which should be in accordance with the specification, and the results are given in Table 1.
Test example 2: determination of content
Measuring according to high performance liquid chromatography (appendix VD), and using octadecylsilane chemically bonded silica as a filler for chromatographic conditions and system applicability tests; methanol-water (10: 90) as a mobile phase; and (3) detecting the wavelength at 254nm, taking 5ml of valacyclovir hydrochloride reference substance solution, adding guanine reference substance storage solution lml under the items of guanine and other related substances, shaking up, taking 20 mu l of the solution, injecting the solution into a liquid chromatograph, and recording a chromatogram, wherein the separation degree of a valacyclovir hydrochloride peak and a guanine peak meets the requirement.
The determination method comprises the following steps: respectively taking about 50mg of the valacyclovir hydrochloride tablet prepared in example 18, precisely weighing, placing the valacyclovir hydrochloride tablet in a 50ml measuring flask, adding 5ml of 0.4% sodium hydroxide solution to dissolve the valacyclovir hydrochloride tablet, diluting the valacyclovir hydrochloride tablet to a scale with water, shaking up, precisely measuring 2ml, placing the valacyclovir hydrochloride tablet in a 100ml measuring flask, diluting the valacyclovir hydrochloride tablet to the scale with water, shaking up, precisely measuring 20 mu l, injecting the valacyclovir hydrochloride tablet into a liquid chromatograph, and recording a chromatogram; taking another appropriate amount of valacyclovir hydrochloride reference substance, and measuring by the same method. Calculating according to the peak area by an external standard method to obtain the product. The results are shown in Table 1.
TABLE 1 dissolution and content measurement results of valacyclovir hydrochloride liposome tablets of each example
| Sample source | Dissolution rate at 5min (%) | 15min dissolution (%) | Content (%) |
| Example 1 | 79.19 | 86.27 | 99.3 |
| Example 2 | 89.16 | 90.18 | 99.5 |
| Example 3 | 97.38 | 98.19 | 99.1 |
| Example 4 | 98.79 | 99.63 | 99.8 |
| Example 5 | 99.42 | 100.03 | 99.9 |
| Example 6 | 99.31 | 99.36 | 99.7 |
| Example 7 | 99.12 | 99.91 | 99.5 |
| Example 8 | 79.42 | 89.03 | 99.1 |
| Example 9 | 95.37 | 96.19 | 99.5 |
As seen from the table, the results of examples 1 and 2 and examples 3 to 8 show that the dissolution rate of valacyclovir hydrochloride liposome tablets is improved by adding sodium chloride powder, and the experiment results of example 3 and examples 4 to 8 prove that the dissolution rate of valacyclovir hydrochloride liposome tablets is improved by increasing the content of sodium chloride powder; as is clear from a comparison of the results of example 9 and examples, sodium bicarbonate is less effective than sodium chloride powder, although it slightly improves the degree of elution; although the addition of the disintegrant contributes to the disintegration of the tablet, the increase of the content of the disintegrant does not exert a good effect of accelerating the disintegration in comparison with examples 2, 5 and 6, and the analysis of each component shows that once a gel layer is formed on the surface layer of the tablet, the internal entry of the aqueous solvent is slowed or prevented, the function of the disintegrant is affected, and even if the content of the disintegrant is increased, the effect is not exerted; the neutral inorganic salt sodium chloride in examples 5 and 6 can change the solubility of the polymer by ionic water interaction, the homogeneous salt of sodium chloride tends to bind with water and form a more ordered water structure, and the ions with higher surface charge density are more competitive with water molecules, thus more effectively salting out the polymer, reducing gelation of the polymer and formation of sticky layers on the tablet surface, and thus achieving disintegration of the tablet. I.e., sodium chloride depresses the cloud point of the polymer and slows its dissolution, thereby delaying the formation of a viscous layer and allowing time for disintegration.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (6)
1. A valacyclovir hydrochloride liposome tablet is characterized in that: the valacyclovir hydrochloride liposome preparation comprises 1 part of valacyclovir hydrochloride liposome, 5-6 parts of filler, 0.1-0.3 part of excipient, 2-5 parts of disintegrant, 2-5 parts of adhesive and 0.5-1 part of lubricant in parts by weight; the valacyclovir hydrochloride liposome consists of valacyclovir hydrochloride, cholesterol, soybean lecithin and polyvinylpyrrolidone-K30, wherein the weight ratio of the valacyclovir hydrochloride to the cholesterol to the soybean lecithin to the polyvinylpyrrolidone-K30 is 1:1-3:5-10: 6-8;
the excipient is sodium chloride powder;
the disintegrating agent is one of croscarmellose sodium or chitin;
the preparation method of the valacyclovir hydrochloride liposome tablet comprises the following steps: (1) preparation of valacyclovir hydrochloride liposome: weighing valacyclovir hydrochloride, cholesterol and soybean lecithin in a certain proportion, dissolving the valacyclovir hydrochloride, the cholesterol and the soybean lecithin in a solvent, removing the solvent on a rotary evaporator at 60 ℃ under a vacuum condition to obtain a film, and continuously evaporating for 2 hours to completely remove all trace solvents and obtain a dry film; hydrating the dry film with a suitable amount of phosphate buffer containing polyvinylpyrrolidone-K30 at 45 deg.C for 15min to obtain a liposome solution; sonicating the obtained liposome for 5 minutes to obtain small and uniform vesicles, and freeze-drying the obtained dry liposome powder and storing at 4 ℃ until use; (2) mixing: adding a proper amount of ethanol into the liposome powder, the filler, the adhesive and the disintegrating agent in the step (1) to prepare a soft material, sieving the soft material with a 24-mesh sieve for granulation, drying the soft material at 55 ℃, and finishing granules of 16 meshes to prepare valacyclovir hydrochloride liposome particles; (3) tabletting: and (3) uniformly mixing the valacyclovir hydrochloride lipidosome particles obtained in the step (2), the excipient and the lubricant in a three-way motion mixer according to an equivalent progressive method, controlling the weight of the tablets, and tabletting to obtain the valacyclovir hydrochloride lipidosome tablets.
2. The liposomal valacyclovir hydrochloride tablet of claim 1, wherein: the filler is microcrystalline cellulose.
3. The liposomal valacyclovir hydrochloride tablet of claim 1, wherein: the adhesive is a polyvinylpyrrolidone/vinyl acetate copolymer.
4. The liposomal valacyclovir hydrochloride tablet of claim 1, wherein: the lubricant is one or more of magnesium stearate, micropowder silica gel and sodium stearyl fumarate.
5. The liposomal valacyclovir hydrochloride tablet of claim 1, wherein: the valacyclovir hydrochloride liposome tablet comprises 1 part of valacyclovir hydrochloride liposome, 6 parts of microcrystalline cellulose, 0.3 part of sodium chloride powder, 2 parts of chitin, 4.4 parts of polyvinylpyrrolidone/vinyl acetate copolymer and 0.8 part of magnesium stearate; the valacyclovir hydrochloride liposome is composed of valacyclovir hydrochloride, cholesterol, soybean lecithin and polyvinylpyrrolidone-K30 in a weight ratio of 1:1:8: 6.
6. The method of preparing a liposomal valacyclovir hydrochloride tablet of claim 1, wherein the method comprises: the solvent in the step (1) is a mixed solution of dichloromethane and methanol in a volume ratio of 3: 1.
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| CN101780232A (en) * | 2010-03-23 | 2010-07-21 | 南昌大学 | Coix seed oil proliposome and preparation method thereof |
| CN103462918A (en) * | 2013-09-22 | 2013-12-25 | 南京正亮医药科技有限公司 | Valaciclovir hydrochloride tablet and preparation method thereof |
| WO2020122244A1 (en) * | 2018-12-14 | 2020-06-18 | 富士フイルム株式会社 | Tablet and method for producing same |
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|---|---|---|---|---|
| CN101780232A (en) * | 2010-03-23 | 2010-07-21 | 南昌大学 | Coix seed oil proliposome and preparation method thereof |
| CN103462918A (en) * | 2013-09-22 | 2013-12-25 | 南京正亮医药科技有限公司 | Valaciclovir hydrochloride tablet and preparation method thereof |
| WO2020122244A1 (en) * | 2018-12-14 | 2020-06-18 | 富士フイルム株式会社 | Tablet and method for producing same |
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| 更昔洛韦脂质体的制备;李凤等;《西北药学杂志》;20071231;第22卷(第6期);第317-319页 * |
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