Monoravir pharmaceutical composition preparation and preparation method thereof

Abstract

The invention provides a Monoravir pharmaceutical composition preparation and a preparation method thereof. The preparation is prepared from monoravir, valine and dextrin. According to the invention, valine and dextrin are used as auxiliary materials of the monoravir tablet or capsule, the two auxiliary materials play an unexpected role in improving the stability of monoravir, and especially, the effect is the best when 12 g of valine and 155 g of dextrin are added into every 200 g of monoravir according to a specific proportion; meanwhile, a mixed solution of povidone K30 and polysorbate 80 is continuously added into the prescription for granulation, so that the dissolution rate can be obviously improved accidentally.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology and relates to a monolavir pharmaceutical composition preparation and a preparation method thereof. Background Art

[0002] Monovir: The chemical name is {(2R,3S,4R,5R)-3,4-dihydroxy-5-[(4Z)-4-(oxime)-2-oxo-3,4-dihydropyrimidin-1(2H)-yl]oxacyclopentane-2-yl}methyl-2-methylpropanoate, with a molecular formula of C 13 H 19 N3O7 is an antiviral drug used to treat adult patients with mild to moderate novel coronavirus infection (COVID-19) with high risk factors for progression to severe illness. Clinically, it has been found that the drug has a certain effect on monkeypox and is currently under clinical research.

[0003] Monkeypox is a zoonotic disease caused by the monkeypox virus that can infect both humans and animals. The monkeypox virus belongs to the genus Orthopoxvirus of the Poxviridae family and is divided into two categories: the West African branch and the Congo Basin branch. People at high risk of the disease are mainly health workers who are exposed to the virus, people who have close contact with monkeypox patients, as well as children, pregnant women, and people with weakened immunity. The main symptoms of monkeypox include fever, swollen lymph nodes, and blisters and pustules all over the body, accompanied by a tendency to bleed. The main sources of infection for monkeypox are infected humans and animals, and it is mainly transmitted through direct contact and respiratory droplets.

[0004] Because of the positive therapeutic effect of Monolavir and the expected efficacy for monkeypox, the study of a more stable Monolavir compound has a positive effect on the application of Monolavir. The inventors unexpectedly obtained a new Monolavir pharmaceutical composition preparation and a preparation method thereof during a long-term and extensive study of Monolavir. The Monolavir composition prepared by the method has extremely high quality stability, increases the safety of medication and the convenience of the preparation, and has positive significance for the clinical application of Monolavir. Summary of the invention

[0005] The object of the present invention is to provide a monolavin preparation with good stability, high solubility and simple preparation process.

[0006] In order to achieve the above object, the present invention adopts the following technical solution:

[0007] In a first aspect of the present invention, a monolavin pharmaceutical composition preparation is provided, the preparation comprising monolavin, valine and dextrin.

[0008] Furthermore, the mass ratio of monolavine, valine and dextrin is 200:(10-14):(150-160).

[0009] Preferably, per 1000 preparation units, the amount of monolavir is 200 g, the amount of valine is 12 g, and the amount of dextrin is 155 g.

[0010] Preferably, the specification of the monolavir pharmaceutical composition preparation is 0.2 g.

[0011] Furthermore, the preparation also includes povidone and polysorbate.

[0012] Furthermore, the mass ratio of monolavin, valine, dextrin, povidone K30 and polysorbate 80 is 200:(10-14):(150-160):(2.5-2.7):(0.4-0.6).

[0013] Preferably, the monolavin pharmaceutical composition formulation may also contain 50 ml of a mixed solution of povidone K30 and polysorbate 80, wherein the mixed solution of povidone K30 and polysorbate 80 is prepared by dissolving 2.6 g of povidone K30 and 0.5 g of polysorbate 80 in purified water and adjusting the volume to 50 ml.

[0014] Preferably, the prescription amount is:

[0015] Each 1000 Monovir tablets or capsules contains:

[0016] Monolavin compound: 200g,

[0017] Valine: 12g,

[0018] Dextrin: 155g,

[0019] Povidone K30: 2.6g,

[0020] Polysorbate 80: 0.5g.

[0021] Furthermore, the preparation is a tablet or a capsule.

[0022] In the second aspect of the present invention, a method for preparing the monolavin pharmaceutical composition is provided, the method comprising:

[0023] Pre-dried monolavine, valine, and dextrin in the prescribed amount are sieved in sequence;

[0024] After fully mixing all the raw and auxiliary materials, the content is determined, and the tablet weight or filling amount is determined according to the specifications. The tablets are pressed into tablets or filled into capsules on a machine, and then inspected and packaged.

[0025] In the third aspect of the present invention, a method for preparing the monolavin pharmaceutical composition is provided, the method comprising:

[0026] Sequentially sieving the pre-dried prescription amounts of monolavine, valine, and dextrin to obtain raw materials and excipients;

[0027] Adding povidone K30 and polysorbate 80 into purified water, stirring to dissolve and fixing the volume to obtain a solution;

[0028] The raw and auxiliary materials are mixed, added into the solution and mixed evenly, sieved and granulated, the content is measured after drying, the tablet weight or filling amount is determined according to the specifications, the tablets are pressed into tablets or filled into capsules, inspected, and packaged to obtain the product.

[0029] Furthermore, the monolavin, valine and dextrin are sieved in sequence using a 80-mesh sieve; and the sieving granulation is performed using a 60-mesh sieve.

[0030] Furthermore, the pre-drying temperature is 64°C-66°C.

[0031] Furthermore, in the content determination after drying, the drying conditions include: drying at 69° C.-71° C. for 1.8-2.2 hours.

[0032] One or more technical solutions provided by the present invention have at least the following technical effects:

[0033] The present invention provides a monolavin pharmaceutical composition preparation and a preparation method thereof. Valine and dextrin are used as excipients of monolavin tablets or capsules. The use of the two excipients has an unexpected effect on increasing the stability of monolavin, especially the best effect of adding 12g of valine and 155g of dextrin in a specific ratio per 200g of monolavin. At the same time, a mixed solution of povidone K30 and polysorbate 80 is continuously added to the prescription for granulation, which can significantly improve the dissolution rate unexpectedly. DETAILED DESCRIPTION

[0034] The present invention will be described in detail below in conjunction with specific implementations and examples, and the advantages and various effects of the present invention will be more clearly presented. It should be understood by those skilled in the art that these specific implementations and examples are used to illustrate the present invention, rather than to limit the present invention.

[0035] Throughout the specification, unless otherwise specifically stated, the terms used herein should be understood as meanings commonly used in the art. Therefore, unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which the present invention belongs. In the event of a conflict, the present specification takes precedence.

[0036] Unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or obtained by existing methods.

[0037] The present application will be described in detail below with reference to embodiments and experimental data.

[0038] Example 1. Monolavir pharmaceutical composition preparation

[0039] 1. The monolavin pharmaceutical composition preparation of the embodiment of the present invention is composed of monolavin, valine and dextrin, and is made into tablets or capsules. For every 1000 preparation units, the amount of monolavin is 200 g, the amount of valine is 12 g, and the amount of dextrin is 155 g.

[0040] 2. Preparation method of tablets:

[0041] (1) Sequentially pass monolavin, valine, and dextrin that have been dried at 65° C. through an 80-mesh sieve;

[0042] (2) After the raw materials and auxiliary materials are fully mixed, their contents are determined, and the tablet weight is determined according to the specifications. The tablets are pressed onto a tabletting machine, inspected, and packaged.

[0043] 3. Preparation method of capsule

[0044] (1) Pre-dried at 65° C., monolavine, valine, and dextrin are sequentially passed through an 80-mesh sieve;

[0045] (2) After fully mixing the raw materials and auxiliary materials, the content is determined, the filling amount is determined according to the specifications, and the capsule shells are filled, inspected, and packaged.

[0046] Example 2, Monolavir pharmaceutical composition preparation

[0047] The monolavin pharmaceutical composition preparation of the embodiment of the present invention is composed of monolavin, valine and dextrin, and is prepared into tablets or capsules. For every 1000 preparation units, the amount of monolavin is 200 g, the amount of valine is 11 g, and the amount of dextrin is 155 g. The preparation method is the same as that of Example 1.

[0048] Example 3, Monolavir pharmaceutical composition preparation

[0049] The monolavin pharmaceutical composition preparation of the embodiment of the present invention is composed of monolavin, valine and dextrin, and is prepared into tablets or capsules. For every 1000 preparation units, the amount of monolavin is 200 g, the amount of valine is 12 g, and the amount of dextrin is 153 g. The preparation method is the same as that of Example 1.

[0050] Example 4, Monolavir pharmaceutical composition preparation

[0051] The monolavin pharmaceutical composition preparation of the embodiment of the present invention is composed of monolavin, valine and dextrin, and is prepared into tablets or capsules. For every 1000 preparation units, the amount of monolavin is 200 g, the amount of valine is 11 g, and the amount of dextrin is 153 g. The preparation method is the same as that of Example 1.

[0052] Example 5. Monolavir pharmaceutical composition preparation

[0053] The monolavin pharmaceutical composition preparation of the embodiment of the present invention is composed of monolavin, valine and dextrin, and is prepared into tablets or capsules. For every 1000 preparation units, the amount of monolavin is 200 g, the amount of valine is 13 g, and the amount of dextrin is 156 g. The preparation method is the same as that of Example 1.

[0054] Comparative Example 1, Monolavir pharmaceutical composition preparation

[0055] In this comparative example, the monolavir pharmaceutical composition preparation is composed of monolavir and dextrin, and is prepared into tablets or capsules, and the amount of monolavir used is 200g and the amount of dextrin used is 155g per 1000 preparation units. The preparation method is the same as that of Example 1.

[0056] Comparative Example 2, Monolavir pharmaceutical composition preparation

[0057] In this comparative example, the monolavir pharmaceutical composition preparation is composed of monolavir and valine, and is prepared into tablets or capsules, and the amount of monolavir used is 200g and the amount of valine used is 12g per 1000 preparation units. The preparation method is the same as that of Example 1.

[0058] Comparative Example 3, Monolavir Pharmaceutical Composition Preparation

[0059] In this comparative example, the monolavir pharmaceutical composition preparation is made of monolavir into tablets or capsules, and the amount of monolavir used per 1000 preparation units is 200 g. The preparation method is the same as that of Example 1.

[0060] Experimental Example 1: Study on the ratio characteristics of excipients of Monolavir tablets and capsules

[0061] The tablets and capsules prepared in the above Examples 1 to 5 and Comparative Examples 1 to 3 were tested. In order to make the technical effect of the combined use of valine and dextrin easier to understand, the following test illustrates the effect of the combined use of valine and dextrin on the content of monolavin tablets and capsules, and the influencing factor test is carried out. The tablets and capsules are placed at 60°C and strong light (4500l x ± 500l x) for 10 days, and samples are taken on the 10th day for testing. The results are compared with those on day 0. The test results are shown in Table 1-2:

[0062] Table 1 Comparative test results of different dosages of valine and dextrin tablets

[0063]

[0064] Table 2 Comparative test results of different dosages of valine and dextrin capsules

[0065]

[0066] From the results in Table 1-2, it can be seen that the combined use of dextrin and valine has a significant effect on the stabilization of the content of the monolavin compound, especially the specific ratio of adding 12g of valine and 155g of dextrin per 200g of monolavin has the best effect.

[0067] Example 6. Monolavir pharmaceutical composition preparation and preparation method thereof

[0068] 1. Prescription:

[0069] Monolavin: 200g, valine: 12g, dextrin: 155g, povidone K30: 2.6g, polysorbate 80: 0.5g.

[0070] 2. Preparation method of tablets:

[0071] 1000 pieces

[0072] (1) Pre-dried at 65° C., monolavine, valine, and dextrin are sequentially passed through an 80-mesh sieve;

[0073] (2) Add povidone K30 and polysorbate 80 into purified water, stir to dissolve and dilute to 50 ml;

[0074] (3) After all the raw and auxiliary materials are fully mixed, the solution prepared in step (2) is added, the mixture is evenly mixed, the mixture is sieved through a 60-mesh sieve, granulated, dried at 70° C. for 2 hours, the content is determined, the tablet weight is determined according to the specification, the tablet is pressed on a machine, inspected, and packaged.

[0075] 3. Preparation method of capsule

[0076] (1) passing the monolavin compound, valine, and dextrin, which have been previously dried at 65° C., through an 80-mesh sieve in sequence;

[0077] (2) Add povidone K30 and polysorbate 80 into purified water, stir to dissolve and dilute to 100 ml;

[0078] (3) After all the raw materials and auxiliary materials are fully mixed, the solution prepared in step (2) is added, mixed evenly, granulated through a 60-mesh sieve, dried at 70° C. for 2 hours, the content is determined, the filling amount is determined according to the specification, filled into capsule shells, inspected, and packaged.

[0079] Example 7. Monolavir pharmaceutical composition preparation and preparation method thereof

[0080] 1. Prescription:

[0081] Monolavin: 200g, valine: 12g, dextrin: 155g, povidone K30: 2.5g, polysorbate 80: 0.5g.

[0082] 2. The preparation method is the same as Example 6.

[0083] Example 8. Monolavir pharmaceutical composition preparation and preparation method thereof

[0084] 1. Prescription:

[0085] Monolavin: 200g, valine: 12g, dextrin: 155g, povidone K30: 2.6g, polysorbate 80: 0.4g.

[0086] 2. The preparation method is the same as Example 6.

[0087] Example 9: Monolavir pharmaceutical composition preparation and preparation method thereof

[0088] 1. Prescription:

[0089] Monolavin: 200g, valine: 12g, dextrin: 155g, povidone K30: 2.5g, polysorbate 80: 0.4g.

[0090] 2. The preparation method is the same as Example 6.

[0091] Example 10. Monolavir pharmaceutical composition preparation and preparation method thereof

[0092] 1. Prescription:

[0093] Monolavin: 200g, valine: 12g, dextrin: 155g, povidone K30: 2.7g, polysorbate 80: 0.55g.

[0094] 2. The preparation method is the same as Example 6.

[0095] Example 11. Monolavir pharmaceutical composition preparation and preparation method thereof

[0096] 1. Prescription:

[0097] Monolavin: 200g, valine: 12g, dextrin: 155g, povidone K30: 2.6g.

[0098] 2. The preparation method is the same as Example 6.

[0099] Experimental Example 2: Study on the properties of a mixed solution of povidone K30 and polysorbate 80 as an adhesive

[0100] The dissolution of the tablets and capsules of Examples 6 to 11 and Example 1 was tested. In order to make the technical effect of the combined use of the mixed solution of povidone K30 and polysorbate 80 easier to understand, the following test was conducted to illustrate the effect of the combined use of povidone K30 and polysorbate 80 on the dissolution of monolavin tablets and capsules. At 37°C, 900 mL of 0.01 M hydrochloric acid solution was used as the dissolution medium, and the paddle method was used at a speed of 50 rpm. The dissolution of the tablets and capsules was measured after 30 minutes. The test results are shown in Table 3-4:

[0101] Table 3 Comparative test results of different prescription amounts of povidone K30 and polysorbate 80 tablets

[0102]

[0103] Table 4 Comparative test results of different prescription amounts of povidone K30 and polysorbate 80 capsules

[0104]

[0105] It can be seen from the results in Tables 3-4 that the combined use of povidone K30 and polysorbate 80 has a significant effect on improving the solubility of the monolavin compound, especially the specific ratio of adding 5.2g of povidone K30 and 1.0g of polysorbate 80 per 200g of monolavin has the best effect.

[0106] Experimental Example 3: Accelerated Test

[0107] The Monovir tablets and Monovir capsules prepared in Example 1 and Example 6 of the present invention were subjected to an accelerated test, and the method is as follows: the samples were placed in a stability test box (40°C ± 2°C, RH 75% ± 5%), and samples were taken at 0, 3, and 6 months, respectively, and the results are shown in Table 5.

[0108] Table 5 Results of accelerated test of Monovir tablets and capsules

[0109]

[0110] It can be seen from the results in Table 5 that the monolavin tablets and capsules prepared by the present invention have good stability and dissolution under accelerated conditions without the need for complex formulation processes.

[0111] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

[0112] Finally, it should be noted that the terms "comprises," "includes," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that includes a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements that are inherent to such process, method, article, or apparatus.

[0113] Although preferred embodiments of the present invention have been described, additional changes and modifications may be made to these embodiments by those skilled in the art once the basic inventive concepts are known. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments and all changes and modifications that fall within the scope of the present invention. Obviously, those skilled in the art may make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. A monolavin pharmaceutical composition preparation, characterized in that: The formulation includes monolavir, valine and dextrin.

2. A monolavin pharmaceutical composition preparation according to claim 1, characterized in that: The mass ratio of monolavin, valine and dextrin is 200:(10-14):(150-160).

3. A monolavir pharmaceutical composition preparation according to claim 1, characterized in that: The formulation also includes povidone and polysorbate.

4. A monolavir pharmaceutical composition preparation according to claim 3, characterized in that: The mass ratio of monolavin, valine, dextrin, povidone K30 and polysorbate 80 is 200:(10-14):(150-160):(2.5-2.7):(0.4-0.6).

5. A monolavir pharmaceutical composition preparation according to claim 1, characterized in that: The preparation is a tablet or a capsule.

6. A method for preparing the monolavir pharmaceutical composition preparation according to any one of claims 1 to 2, characterized in that: The method comprises: Pre-dried prescription amounts of monolavine, valine, and dextrin are sieved in sequence; After fully mixing the raw and auxiliary materials, the content is determined, and the tablet weight or filling amount is determined according to the specifications. The tablets are pressed into tablets or filled into capsules on a machine, and then inspected and packaged.

7. A method for preparing the monolavir pharmaceutical composition preparation according to any one of claims 3 to 5, characterized in that: The method comprises: Sequentially sieving the pre-dried prescription amounts of monolavine, valine, and dextrin to obtain raw materials and excipients; Adding povidone K30 and polysorbate 80 into purified water, stirring to dissolve and fixing the volume to obtain a solution; The raw and auxiliary materials are mixed, added into the solution and mixed evenly, sieved and granulated, the content is measured after drying, the tablet weight or filling amount is determined according to the specifications, the tablets are pressed into tablets or filled into capsules, inspected, and packaged to obtain the product.

8. The method for preparing the monolavir pharmaceutical composition preparation according to claim 7, characterized in that: The monolavin, valine and dextrin are sieved in sequence, and a 80-mesh sieve is selected; and a 60-mesh sieve is selected in the sieving granulation.

9. The method for preparing the monolavir pharmaceutical composition preparation according to claim 7, characterized in that: The pre-drying temperature is 64°C-66°C.

10. The method for preparing the monolavir pharmaceutical composition preparation according to claim 7, characterized in that: In the determination of the content after drying, the drying conditions include: drying at 69° C.-71° C. for 1.8-2.2 hours.

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