CN114652811A - Compound tablet containing nelmavir and ritonavir - Google Patents
Compound tablet containing nelmavir and ritonavir Download PDFInfo
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Abstract
The invention discloses a compound tablet of nelmavir and ritonavir, which is a core-spun tablet, the tablet-in-tablet technology is adopted to control the drug delivery sequence, and through the combination of two layers of different drug release rates, a more ideal drug release rate can be obtained, the expected blood concentration can be achieved, the stable and long-term effective concentration can be maintained, the toxic effect of the drug is reduced, and adverse reactions such as irritation to gastric mucosa and the like are avoided. This technology combines the advantages of two single formulations. Not only can ensure the dissolution of the medicine, but also can ensure the stability of the packaged medicine. Compared with the existing preparation which needs to be taken multiple tablets at one time and cannot ensure that the nemadefovir can maintain the treatment concentration for a long time, the preparation can release the drug stably for a long time, greatly improves the in-vitro dissolution speed of the nemadefovir and the ritonavir, solves the problems of low dissolution, short action time and the need of taking multiple tablets in the prior art, enhances the treatment effect of the drug, prolongs the treatment time of the drug and simultaneously improves the drug taking compliance of patients.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a compound tablet containing nelmavir and ritonavir and a preparation method thereof.
Background
Coronaviruses are a large family of viruses known to cause the common cold and more serious diseases such as Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS). The novel coronavirus is a new strain of coronavirus.
Coronaviruses (CoV) belong to the family of nidovirales coronaviridae, are enveloped single-stranded, positive-stranded RNA viruses, and are classified into three genera, α, β, and γ. The coronavirus particles are spherical or irregular, have capsule membrane, and have size of 80-120 nm. The 5' end of its genome carries a cap structure, which then contains 6-10 Open Reading Frames (ORFs). The first reading frame occupying genome 2/3 encodes a replicase, and the other 1/3 of the genome encodes mainly structural proteins, typically including spike, S, envelope, E, membrane, M, and nucleoprotein (N). The E protein and the M protein are mainly involved in the assembly process of the virus, and the N protein wraps the genome to form a nucleoprotein complex.
Coronaviruses mediate viral invasion and determine viral tissue or host tropism primarily through the binding of Spike glycoproteins (spyceroproteins) to host cell receptors. Spike glycoproteins (S proteins) are a large class of trimeric transmembrane glycoproteins that form a special corona structure on the surface of the virus, and coronaviruses are therefore named. The S protein, which recognizes host cell receptors and mediates membrane fusion, is critical for entry of viral particles into cells and is a key factor for viral infection of host cells. SARS-CoV-2, like the SARS virus of 2003, enters cells by recognizing the ACE2 protein of the human host. In particular, the cell Receptor Binding Domain (RBD) of the S protein domain is directly involved in host Receptor recognition, and amino acid variation in this region results in changes in viral species tropism and infection characteristics. Therefore, obtaining the complex structure of the S protein of SARS-CoV-2 and ACE2 protein will help to understand the difference between the binding of SARS virus and ACE2 by the novel coronavirus and the existence state of the S protein of SARS-CoV-2 binding to ACE 2. Therefore, the complex structure of the S protein of SARS-CoV-2 and the ACE2 protein provides an important structural biological basis for further precise vaccine design and discovery of antiviral drugs.
In order to cope with global epidemic situation, Molnnapiarvir which resists the merck of new coronary medicine is firstly listed, and then the compound preparation of the paris Paxlovid with better curative effect is followed, and other 18 new coronary therapeutic medicines of domestic and foreign enterprises are in the stage of clinical research of I-III or the stage of reporting to be listed. At present, China effectively controls the spread of new coronavirus based on civil injection vaccine and powerful isolation measures; however, the new coronary cases are these volts internationally, and the patient population is huge.
Paxlovid is a compound preparation packaged by combining a nemadevir tablet and a ritonavir tablet, the specifications of the Paxlovid are 150mg and 100mg respectively, and the Paxlovid is developed by a pfeiffer pharmaceutical. The indications are for treating new coronavirus infection, can be used for high-risk susceptible people (suffering from heart disease, diabetes, immune system deficiency or obesity and old people), and need to be used within 3-5 days after new coronary symptoms appear. The clinical effect of stage III is: in Paxlovid group, 0.8% (3/389) of patients required hospitalization within 28 days, and this ratio was 7.0% (27/385) in the control group. Moreover, 7 patients died in the control group, and the number of cases of death in the Paxlovid group was 0.
The Nemantyvir tablet is a SARS-CoV-2 protease inhibitor, and is packaged together with ritonavir tablet. Ritonavir itself is inactive against SARS-CoV-2 and inhibits CYP 3A-mediated metabolism of the nemadevir tablets, thereby increasing the plasma concentration of the nemadevir to a level expected to inhibit SARS-CoV-2 replication. However, the combined packaged medicine is taken by two medicines simultaneously, the two medicines are released quickly after entering a human body, the acting time of the intestinal tract is short, the effect of the nemadevir in inhibiting the reproduction of SARS-CoV-2 can not be exerted for a long time, and the ideal antiviral effect can not be achieved.
Disclosure of Invention
The invention aims to solve the problems that the prior preparation needs to be taken for a plurality of tablets at one time, cannot ensure that the treatment concentration of the nemadevir is maintained for a long time, and has insufficient action time. The preparation method comprises the steps of preparing a core-spun tablet of the nelmavir and the ritonavir, controlling a drug delivery sequence by adopting a tablet-in-tablet technology, sequentially providing the ritonavir which is immediately released and the nelmavir which is delayed to be released, obtaining an ideal drug release rate by combining two layers of different drug release rates, achieving an expected blood concentration, having a long action time, maintaining a stable and long-term effective concentration, reducing the toxic effect of the drug, and avoiding adverse reactions such as irritation to gastric mucosa. The ritonavir which is released rapidly can inhibit the enzymatic activity for degrading the nemadefovir, and then the nemadefovir is dissolved and released, so the metabolic rate of the nemadefovir is greatly reduced, the plasma concentration of the nemadefovir is maintained at the level which can be expected to inhibit the replication of SARS-CoV-2, and the effect of treating the new coronavirus infection is achieved. This technique combines the advantages of two single formulations. Not only can ensure the dissolution of the medicine, but also can ensure the stability of the packaged medicine. Compared with the existing preparation which needs to be taken for multiple tablets at one time and cannot ensure that the nemadefovir can maintain the treatment concentration for a long time, the preparation adopts the tablet-in-tablet drug release technology, can release drugs stably for a long time, keeps the effective drug concentration of the drugs in vivo for a long time, greatly improves the in-vitro dissolution speed of the nemadefovir and ritonavir, improves the drug effect and the safety degree, solves the problems of low dissolution, short action time and the need of taking multiple tablets in the prior art, enhances the drug treatment effect, prolongs the drug treatment time, improves the drug taking compliance of patients (reduces the drug taking frequency) and reduces the peak-valley phenomenon of the blood concentration.
The compound tablet is a compound tablet of the nelmavir and the ritonavir, and is prepared by adopting a core-spun tablet pressing technology, the method is a novel tabletting method, and the core-spun tablet obtained by the method has small tablet weight difference and uniform drug content. The required device is mainly a tablet press capable of pressing core-spun tablets. Compared with the combined packaging dosage form on the market at present, the method has simple process, does not need to carry out independent multiple tabletting and coating, and can save the production cost. At present, the combined packaging preparation formulation on the market has the problems that the dissolution of the medicine is unstable, a plurality of medicines need to be taken at one time, the medicine release is unstable, the long-term maintenance of the treatment concentration of the nemadefovir can not be ensured and the like because two single medicines are combined, packaged and sold, and the invention can avoid the problems.
Compared with the common medicine combination packaging dosage form, the core-spun tablet technology has the advantages that when the medicine is taken, the outer layer component of the core-spun tablet is immediately released, the medicine component of the inner core tablet, namely the nemadevir, is delayed to release, the medicine is completely absorbed, and therefore the bioavailability is improved. Through the combination of two layers of different drug release rates, a more ideal drug release rate can be obtained, the expected blood drug concentration can be achieved, the stable and long-term effective concentration can be maintained, the toxic effect of the drug is reduced, and adverse reactions such as irritation to gastric mucosa and the like are avoided. The two different components are compressed into tablets which are not mixed with each other, so that the stability of the medicine can be improved. The process of the core-spun tablet prepared by coating the outer layer in a tabletting way is more reliable than the process of directly coating the surface of the tablet, and the problems of medicine leakage and the like caused by uneven direct coating of the tablet can be avoided.
Specifically, the purpose of the invention is realized by the following technical scheme:
the invention discloses a core-spun tablet of nelmavir and ritonavir, which is prepared by firstly preparing active ingredients of the nelmavir, a filling agent, a disintegrating agent, a flow aid, a lubricating agent and the like into micro-tablets, then coating an isolating layer, pressing the micro-tablets and a coating layer prepared from another active ingredient of the ritonavir into core-spun tablets, and finally coating.
A core-spun tablet of nelmavir and ritonavir comprises a nelmavir mini-tablet and a ritonavir wrapping layer; the core-spun sheet comprises the following components in parts by mass:
the composition of the nemadevir micro-tablets is as follows:
ritonavir wrapping layer composition:
preferably, the filler is selected from one or more of corn starch, lactose monohydrate, microcrystalline cellulose, anhydrous dicalcium phosphate, calcium carbonate and dicalcium phosphate.
Preferably, the disintegrant is selected from one or more of crospovidone, croscarmellose sodium, sodium carboxymethyl starch and low substituted hydroxypropyl cellulose.
Preferably, the glidant is selected from one or more of colloidal silicon dioxide and talcum powder.
Preferably, the lubricant is selected from one or more of magnesium stearate, sodium fumarate stearate, zinc stearate, stearic acid and calcium stearate.
Preferably, the carrier polymer is selected from one or more of polycaprolactone polyol, copovidone, polyurethane and polyethylene terephthalate.
Preferably, the surfactant is selected from one or more of polysorbate, sorbitol laurate, lauryl sorbitan, sodium dodecyl sulfate, span and monolauryl phosphate.
The invention also provides a preparation method of the core-spun tablets of the nelmavir and the ritonavir, which comprises the following steps:
(1) preparing a nemadevir micro-tablet: uniformly mixing the nemadevir, the filling agent, the disintegrating agent, the glidant and the 1/2 lubricant according to the formula amount by adopting an equivalent incremental method; performing dry granulation to obtain granules; adding 1/2 lubricant, mixing to obtain mixed granule; selecting a round punch die for tabletting to obtain the nemadefovir dipivoxil micro tablet. Then an isolation layer is wrapped.
(2) Preparing a ritonavir wrapping layer: carrying out hot-melt extrusion granulation on the ritonavir, the carrier polymer, the surfactant and the flow aid in the formula amount of 1/2 to obtain an intermediate product of the ritonavir; and then grinding the ritonavir extrusion intermediate product, and uniformly mixing the ground material, the filling agent, the lubricating agent and the flow aid according to the formula amount of 1/2 to obtain a ritonavir coating layer.
(3) Tabletting and coating: selecting a circular die, pressing the nelmavir mini-tablets coated with the isolating layer and the ritonavir coating layer into core-spun tablets, and then coating to finally obtain the compound tablet containing the nelmavir and the ritonavir.
As a preferable scheme of the invention, the composition of the isolating layer in the step (2) is polyethylene glycol, and the weight of the isolating layer is increased by 0.5-1.5%.
As a preferable scheme of the invention, the coating in the step (4) is to coat by using a film coating premix, and the weight of the coating is increased by 1-5%.
Compared with the prior art, the invention has the following beneficial effects:
the core-spun tablets containing the nelmavir and the ritonavir provided by the invention have stable drug dissolution, long-acting release, improved drug utilization rate, prolonged drug action time and long-term effective treatment concentration maintenance. The preparation process is simple, the quality and the curative effect of the medicine are ensured, and the toxic and side effects are reduced.
The tablet still has good stability under the environment of 60 ℃/RH 75% after 30-day accelerated test.
Detailed Description
The invention will be further illustrated and described with reference to specific embodiments. The technical features of the embodiments of the present invention can be combined correspondingly without mutual conflict.
Example 1:
the preparation method comprises
(1) Preparing a nemadevir micro-tablet:
uniformly mixing the nemadevir, the microcrystalline cellulose, the croscarmellose sodium, the colloidal silicon dioxide and the sodium stearyl fumarate according to the formula amount of 1/2 by adopting an equivalent progressive method;
dry granulating the mixture to obtain granules; 1/2 sodium stearyl fumarate with formula amount is added and mixed evenly to prepare total mixed particles;
selecting a round punch die for tabletting to obtain the nemadefovir dipivoxil micro tablet.
The nemadevir mini-tablet comprises an isolation layer: adding purified water into the slurry mixing tank, starting stirring, slowly adding the polyethylene glycol according to the formula amount, and stirring for more than 30 minutes until the solution is clear. Pouring the nemadefovir dipivoxil tablets into a coating pan to wrap an isolation layer, and in the liquid spraying process, stabilizing the temperature of the tablet core at 25 +/-5 ℃ and controlling the weight gain of the isolation layer to be 0.5-1.5%.
(2) Preparing a ritonavir wrapping layer: carrying out hot-melt extrusion granulation on ritonavir, copovidone, sorbitol laurate and 1/2 colloidal silicon dioxide in the formula amount to obtain an intermediate product of the ritonavir; and then, grinding the ritonavir extrusion intermediate product, and mixing the ground material with anhydrous calcium hydrophosphate, sodium stearyl fumarate and 1/2 formula amount of colloidal silicon dioxide to obtain a ritonavir coating layer.
(3) Tabletting and coating: selecting a circular punch die, pressing the nemadefovir dipivoxil micro tablets coated with the isolation layer and the ritonavir coating layer into core-coated tablets, and finally coating with a film coating premix according to the formula amount, wherein the temperature of the tablet core is controlled to be 50 +/-5 ℃, and the weight gain of the coating is controlled to be 1-5%. Finally preparing the compound tablet containing the nelmavir and the ritonavir.
It should be noted that, as an alternative implementation manner of this embodiment, the microcrystalline cellulose and anhydrous calcium hydrogen phosphate of the filler may also be replaced by corn starch, lactose and calcium carbonate; the croscarmellose sodium of the disintegrant can also be replaced by sodium carboxymethyl starch, crospovidone and low-substituted hydroxypropyl cellulose; the colloidal silicon dioxide of the glidant can also be replaced by talcum powder; the sodium stearate fumarate of the lubricant can be replaced by magnesium stearate, zinc stearate, stearic acid and calcium stearate; the sorbitol laurate of the surfactant can be replaced by span and polysorbate.
The technical effects of the above alternative technical solutions are not obviously different from those of the present embodiment.
Comparative example 1:
the preparation method comprises
(1) Preparing the nemadevir granules:
uniformly mixing the nemadevir, the microcrystalline cellulose, the croscarmellose sodium, the colloidal silicon dioxide and the sodium stearyl fumarate according to the formula amount of 1/2 by adopting an equivalent progressive method;
dry granulating the mixture to obtain granules; adding 1/2 sodium stearyl fumarate, and mixing to obtain Nemadeiwei granule;
(2) preparation of ritonavir granules:
carrying out hot-melt extrusion granulation on ritonavir, copovidone, sorbitol laurate and 1/2 colloidal silicon dioxide in the formula amount to obtain an intermediate product of the ritonavir; and then, the ritonavir extrusion intermediate product is ground, and the ground material is mixed with anhydrous calcium hydrophosphate, sodium stearyl fumarate and 1/2 formula amount of colloidal silicon dioxide to obtain ritonavir particles.
(3) Tabletting and coating: selecting a circular punch die, pressing the nelmaverir granules and the ritonavir granules into a double-layer tablet, and finally coating with a film coating premix according to the formula amount, wherein the temperature of the tablet core is controlled to be 50 +/-5 ℃, and the weight gain of the coating is controlled to be 1-5%. Finally, a bilayer tablet containing the nelmavir and the ritonavir is prepared.
Comparative example 2:
the preparation method comprises
(1) Preparing a nemadevir tablet:
uniformly mixing the nemadevir, the microcrystalline cellulose, the croscarmellose sodium, the colloidal silicon dioxide and the sodium stearyl fumarate according to the formula amount of 1/2 by adopting an equivalent progressive method;
dry granulating the mixture to obtain granules; adding 1/2 sodium stearyl fumarate, and mixing to obtain Nemadeiwei granule;
selecting a round die, pressing the nemadefovir granules into tablets, and then coating. Coating with film coating premix according to the formula amount, wherein the temperature of a tablet core is controlled to be 50 +/-5 ℃, and the weight gain of the coating is controlled to be 1-5%.
(2) Preparation of ritonavir tablets:
carrying out hot-melt extrusion granulation on ritonavir, copovidone, sorbitol laurate and 1/2 colloidal silicon dioxide in the formula amount to obtain an intermediate product of the ritonavir; and then, the ritonavir extrusion intermediate product is ground, and the ground material is mixed with anhydrous calcium hydrophosphate, sodium stearyl fumarate and 1/2 formula amount of colloidal silicon dioxide to obtain ritonavir particles.
A round die was selected to compress the ritonavir granules into tablets, which were then coated. Coating with film coating premix according to the formula amount, wherein the temperature of a tablet core is controlled to be 50 +/-5 ℃, and the weight gain of the coating is controlled to be 1-5%.
(3) Packaging: and carrying out combined packaging on the nelmavir tablets and the ritonavir tablets to finally prepare a combined packaging preparation containing the nelmavir and the ritonavir.
Comparative example 3:
the preparation method comprises
(1) Preparing a nemadevir micro-tablet:
uniformly mixing the nemadevir, the microcrystalline cellulose, the croscarmellose sodium, the colloidal silicon dioxide and the sodium stearyl fumarate according to the formula amount of 1/2 by adopting an equivalent progressive method;
dry granulating the mixture to obtain granules; 1/2 sodium stearyl fumarate with formula amount is added and mixed evenly to prepare total mixed particles;
and (4) selecting a circular punch die for tabletting to obtain the nemadevir mini-tablet plain tablets.
The nemadevir mini-tablet is coated with an isolating layer: adding purified water into the slurry mixing tank, starting stirring, slowly adding the polyethylene glycol according to the formula amount, and stirring for more than 30 minutes until the solution is clear. Pouring the nemadefovir dipivoxil tablets into a coating pan to wrap an isolation layer, and in the liquid spraying process, stabilizing the temperature of the tablet core at 25 +/-5 ℃ and controlling the weight gain of the isolation layer to be 0.5-1.5%.
(4) Preparing a ritonavir wrapping layer: carrying out hot-melt extrusion granulation on ritonavir, copovidone, sorbitol laurate and 1/2 colloidal silicon dioxide in the formula amount to obtain an intermediate product of the ritonavir; and then, extruding the ritonavir intermediate product for grinding, and mixing the ground material with anhydrous calcium hydrophosphate, sodium stearyl fumarate and 1/2 formula amount of colloidal silicon dioxide to obtain a ritonavir coating layer.
(5) Tabletting and coating: selecting a circular punch die, pressing the nemadefovir dipivoxil micro tablets coated with the isolation layer and the ritonavir coating layer into core-coated tablets, and finally coating with a film coating premix according to the formula amount, wherein the temperature of the tablet core is controlled to be 50 +/-5 ℃, and the weight gain of the coating is controlled to be 1-5%. Finally preparing the compound tablet containing the nelmavir and the ritonavir. And (3) yield comparison:
| sample source | Intermediate productYield of the product | Overall yield of |
| Example 1 | 96.4％ | 92.4％ |
| Comparative example 1 | 96.2％ | 91.1％ |
| Comparative example 2 | 95.8％ | 93.1％ |
| Comparative example 3 | 95.9％ | 91.8％ |
The yields of example 1 and comparative examples 1, 2 and 3 were within the required ranges.
And (3) dissolution detection:
the solution preparation method of the test sample comprises the following steps: according to the general rules for determination of dissolution and release (second method 0931 of the general rules of the "Chinese pharmacopoeia"), the results are shown in the following table (in nemadevir):
from the experimental results in the table above, it can be known that the core-spun tablets of nelmavir and ritonavir prepared in example 1 and comparative example 3 of the present invention are uniformly and stably dissolved in the medium with ph1.2, and can ensure complete release and dissolution of the drug, maintain the release time of 12h, and maintain the sustained and long-lasting therapeutic effect. In comparative examples 1 and 2, the drug nemadefovir is dissolved out quickly in the early stage, at the moment, ritonavir does not play a role in inhibiting and degrading the enzyme activity of the nemadefovir, the drug nemadefovir is basically and completely dissolved out in 4 hours, the attachment time of the digestive tract is 3-4 hours, the treatment action time is shorter than 12 hours of example 1, and the nemadefovir cannot play a treatment effect in a timely and long-acting manner.
Stability related substance assay (60 ℃/75% RH):
from the above results, it can be seen that the substances of example 1 and comparative example 3 meet the internal control standards under accelerated conditions, and the impurities grow slowly. Compared with the related substance growth conditions of comparative example 1 and comparative example 2, the impurities of example 1 and comparative example 3 grow slowly, change less and are obviously better than those of comparative example 1 and comparative example 2. After 30-day accelerated test, the 30-day stability of the example 1 and the comparative example 3 is qualified; the 30-day stability of comparative example 1 did not meet the internal control criteria; the 30-day stability of comparative example 2 meets the criteria, but each impurity grows more rapidly than in example 1. It follows that the tablets obtained in example 1 and comparative example 3 have good stability in an environment of 60 c/75% relative humidity, after 30 days of accelerated testing.
Claims (10)
1. The compound tablet of the nelmavir and the ritonavir is characterized in that the compound tablet is a core-spun tablet, a tablet core of the core-spun tablet is a nelmavir micro-tablet, and a wrapping layer contains the ritonavir.
2. The combination of nelmavir and ritonavir tablet as claimed in claim 1, wherein the nelmavir mini-tablets are coated with a separation layer, the nelmavir mini-tablets coated with the separation layer are compressed with granules containing ritonavir into core-coated tablets, and the core-coated tablets are further coated to obtain the combination of nelmavir and ritonavir tablet.
3. The composite tablet of nelmavir and ritonavir as claimed in claim 1, wherein the core-spun tablet comprises the following components by mass:
the nemadevir mini-tablets comprise:
ritonavir wrapping layer composition:
4. the compound tablet of nelmavir and ritonavir as claimed in claim 3, wherein: the filler is selected from one or more of corn starch, lactose monohydrate, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, anhydrous dicalcium phosphate, calcium carbonate and calcium hydrogen phosphate.
5. The compound tablet of nelmavir and ritonavir as claimed in claim 3, wherein: the disintegrant is selected from one or more of crospovidone, croscarmellose sodium, sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose.
6. The compound tablet of nelmavir and ritonavir as claimed in claim 3, wherein: the glidant is selected from one or more of colloidal silicon dioxide and talcum powder.
7. The compound tablet of nelmavir and ritonavir as claimed in claim 3, wherein: the lubricant is selected from one or more of magnesium stearate, sodium fumarate stearate, zinc stearate, stearic acid and calcium stearate.
8. The compound tablet of nelmavir and ritonavir as claimed in claim 3, wherein: the carrier polymer is selected from one or more of polycaprolactone polyol, copovidone, polyurethane and polyethylene terephthalate.
9. The compound tablet of nelmavir and ritonavir as claimed in claim 3, wherein: the surfactant is one or more selected from polysorbate, sorbitol laurate, lauryl sorbitan, sodium dodecyl sulfate, span and monolauryl phosphate.
10. A process for the preparation of a combination tablet comprising nelmavir and ritonavir as claimed in claim 1 or 2, comprising the steps of:
(1) preparing a nemadevir micro-tablet: uniformly mixing the nemadevir, the filler, the disintegrant, the glidant and the lubricant according to the formula amount of 1/2 by adopting an equivalent progressive method; performing dry granulation to obtain granules; adding 1/2 lubricant, mixing to obtain mixed granule; selecting a round punch die for tabletting to prepare a nemadefovir dipivoxil mini tablet; the nemadefovir dipivoxil plain tablets are wrapped by an isolation layer;
(2) preparing a ritonavir wrapping layer: carrying out hot-melt extrusion granulation on the ritonavir, the carrier polymer, the surfactant and the flow aid in the formula amount of 1/2 to obtain an intermediate product of the ritonavir; then, grinding the ritonavir extrusion intermediate product, and uniformly mixing the ground material with a filling agent, a lubricant and a glidant in a formula amount of 1/2 to obtain a ritonavir coating layer;
(3) tabletting and coating: selecting a circular die, pressing the nelmavir mini-tablets coated with the isolating layer and the ritonavir coating layer into core-spun tablets, and then coating to finally obtain the compound tablet containing the nelmavir and the ritonavir.
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| CN202210305508.7A CN114652811B (en) | 2022-03-25 | 2022-03-25 | Compound tablet containing nemaltevir and ritonavir |
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| CN202210305508.7A CN114652811B (en) | 2022-03-25 | 2022-03-25 | Compound tablet containing nemaltevir and ritonavir |
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| CN114652811B CN114652811B (en) | 2024-07-05 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115501229A (en) * | 2022-09-07 | 2022-12-23 | 上海复星医药产业发展有限公司 | A Chinese medicinal composition for treating new coronary pneumonia and its preparation method |
| CN116370418A (en) * | 2023-02-22 | 2023-07-04 | 合肥医工医药股份有限公司 | Nemacavir ritonavir compound preparation and preparation method thereof |
| WO2024165081A1 (en) * | 2023-02-08 | 2024-08-15 | 南通市海门品尚医药科技有限公司 | Liquid preparation containing nirmatrelvir and ritonavir, and preparation method therefor and use thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101601641A (en) * | 2008-06-11 | 2009-12-16 | 重庆华邦制药股份有限公司 | A kind of medical solid compound preparation and preparation method thereof |
| CN111939137A (en) * | 2019-05-16 | 2020-11-17 | 上海迪赛诺药业股份有限公司 | Compound tablet containing atazanavir and ritonavir and preparation method thereof |
| CN113925838A (en) * | 2021-11-11 | 2022-01-14 | 乐普制药科技有限公司 | Compound sustained-release tablet of epalrestat and sitagliptin or pharmaceutically acceptable salt thereof and preparation method thereof |
-
2022
- 2022-03-25 CN CN202210305508.7A patent/CN114652811B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101601641A (en) * | 2008-06-11 | 2009-12-16 | 重庆华邦制药股份有限公司 | A kind of medical solid compound preparation and preparation method thereof |
| CN111939137A (en) * | 2019-05-16 | 2020-11-17 | 上海迪赛诺药业股份有限公司 | Compound tablet containing atazanavir and ritonavir and preparation method thereof |
| CN113925838A (en) * | 2021-11-11 | 2022-01-14 | 乐普制药科技有限公司 | Compound sustained-release tablet of epalrestat and sitagliptin or pharmaceutically acceptable salt thereof and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 王欢等: "口服新型冠状病毒肺炎治疗新药——Paxlovid", 《临床药物治疗杂志》, pages 13 - 17 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115501229A (en) * | 2022-09-07 | 2022-12-23 | 上海复星医药产业发展有限公司 | A Chinese medicinal composition for treating new coronary pneumonia and its preparation method |
| WO2024165081A1 (en) * | 2023-02-08 | 2024-08-15 | 南通市海门品尚医药科技有限公司 | Liquid preparation containing nirmatrelvir and ritonavir, and preparation method therefor and use thereof |
| CN116370418A (en) * | 2023-02-22 | 2023-07-04 | 合肥医工医药股份有限公司 | Nemacavir ritonavir compound preparation and preparation method thereof |
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| CN114652811B (en) | 2024-07-05 |
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