Desmopressin acetate tablet composition and preparation method thereof

Abstract

The invention belongs to the field of pharmaceutical preparation preparation, and particularly relates to a desmopressin acetate tablet composition and a preparation method thereof, the desmopressin acetate tablet composition comprises desmopressin acetate, and a filler, an adhesive, a disintegrating agent and a lubricant which form neutral auxiliary materials. The invention further provides a preparation method of the desmopressin acetate tablet, a conventional wet granulation process is adopted, the process is simple, the process duration is short, large-scale production is easy, the time of materials in a high-temperature and high-humidity state in the whole preparation process is short, the impurity content of the desmopressin acetate tablet is reduced, and the stability is good.

Description

Technical Field

[0001] The present invention belongs to the field of preparation of pharmaceutical preparations, and particularly relates to a desmopressin acetate tablet composition and a preparation method thereof. Background Art

[0002] Desmopressin acetate tablets ( Minirin) was developed by Ferring International Center SA and is used for the treatment of central diabetes insipidus and nocturnal enuresis in patients six years of age or older. It was approved for marketing in Sweden in 1987 and approved for import and marketing in China in June 1995.

[0003] Desmopressin acetate is a polypeptide drug, which is a structural analogue of natural arginine vasopressin, that is, the amino group of 1-cysteine is removed and 8-L-arginine is replaced by 8-D-arginine. Therefore, it is also called desmopressin acetate. Desmopressin acetate tablets ( Minirin) are prone to hydrolysis to generate impurities under high temperature and high humidity conditions, resulting in poor stability of desmopressin acetate during the preparation process of the preparation and easy over-standard of impurity content. The excipients of the commercially available preparation are lactose monohydrate, potato starch, polyvinylpyrrolidone, and magnesium stearate. Among them, the excipients for granulation are all acidic excipients, and the material environment during the process is an acidic environment, which is prone to hydrolysis to generate impurities, resulting in higher requirements for the control of humidity and temperature in the preparation process. Therefore, it is necessary to find a desmopressin acetate tablet with a simple preparation process and good stability during the preparation process of the preparation.

[0004] CN1826099A discloses a desmopressin acetate tablet composition and a preparation method thereof. The excipients of this method are lactose monohydrate, potato starch, polyvinylpyrrolidone, and magnesium stearate, and the wetting agent is a 1:3 mixture of water / ethanol. The "one-pot" equipment is used for wet granulation. In this method, a mixed solution of water and ethanol is used as the granulating liquid during the process, and the tablets inevitably contain solvent residues, and the process is relatively complex, with a long process duration and high cost.

[0005] CN1901886A discloses another desmopressin acetate tablet composition and a preparation method thereof. The excipients of this method are lactose monohydrate, potato starch, polyvinylpyrrolidone, and magnesium stearate, and the wetting agent is water. The fluidized bed equipment is used for wet granulation. This method uses water as the wetting agent, although it reduces the explosion risk and contact with organic solvents, but the material is in a hot and humid state for a long time, and the impurity content is prone to exceed the standard.

[0006] CN102423485A discloses another desmopressin acetate tablet composition and its preparation method. A composition containing desmopressin acetate, a polymer excipient, and a surfactant is made into sustained-release microsphere particles; then it is mixed with a composition containing lactose and cellulose, a solubilizer, a penetration enhancer, a flavoring agent, an antioxidant, and a lubricant to make tablets. This method has a complex and cumbersome process, which is not conducive to large-scale production. Summary of the Invention

[0007] In view of the above problems existing in the prior art, the object of the present invention is to establish a desmopressin acetate tablet composition and its preparation method. The desmopressin acetate tablets obtained by the present invention significantly improve the stability of the drug and effectively inhibit the problem that the impurities in the production process of desmopressin acetate tablets are likely to exceed the standard. In addition, on the premise of ensuring the drug stability, the process is simple and the cost is low.

[0008] The present invention provides a desmopressin acetate tablet composition, and its components and contents are by weight percentage:

[0009] Active ingredient desmopressin acetate 0.05% - 0.1%, filler as the neutral excipient 89% - 95%, binder 1% - 5%, disintegrant 1% - 5%, and lubricant 0.2% - 1.0%;

[0010] The filler is one or more of mannitol, microcrystalline cellulose, pregelatinized starch, and corn starch; the binder is one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, and sodium carboxymethylcellulose; the disintegrant is one or more of cross-linked povidone, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethylcellulose, and sodium carboxymethyl starch; the lubricant is one or more of magnesium stearate, stearic acid, silicon dioxide, sodium stearyl fumarate, and talc powder.

[0011] In some embodiments, the filler is a mixture of mannitol and microcrystalline cellulose; mannitol accounts for 45 - 75% of the components, and the microcrystalline cellulose accounts for 20 - 50% of the components.

[0012] In some embodiments, the binder is hydroxypropyl cellulose; hydroxypropyl cellulose accounts for 1 - 5% of the components.

[0013] In some embodiments, the disintegrant is cross-linked sodium carboxymethylcellulose; cross-linked sodium carboxymethylcellulose accounts for 1 - 5% of the components.

[0014] In some embodiments, the lubricant is magnesium stearate; magnesium stearate accounts for 0.2 - 1.0% of the components.

[0015] The present invention also provides a preparation method of desmopressin acetate tablets, including:

[0016] Step 1: Add the filler, disintegrant, and binder into a wet granulator and mix evenly.

[0017] Step 2: Dissolve desmopressin acetate in the wetting agent.

[0018] Step 3: Add the granulating liquid prepared in Step 2 into the wet granulator in Step 1, mix while adding, and then mix for another 2 - 4 min at room temperature after adding.

[0019] Step 4: After wet screening the wet granules obtained in Step 3 through a screening machine, transfer them to a fluidized bed for drying at a drying temperature of 40 - 50 °C for a drying duration of 20 - 60 min.

[0020] Step 5: After screening the dry granules obtained in Step 4 through a screening machine, mix them evenly with the lubricant.

[0021] Step 6: Compress the total mixed granules obtained in Step 5 into tablets.

[0022] In some embodiments, by weight percentage: filler 89% - 95%, binder 1% - 5%, disintegrant 1% - 5%, and lubricant 0.2% - 1.0%; the filler is one or more of mannitol, microcrystalline cellulose, pregelatinized starch, and corn starch; the binder is one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, and sodium carboxymethylcellulose; the disintegrant is one or more of crospovidone, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethylcellulose, and sodium carboxymethyl starch; the lubricant is one or more of magnesium stearate, stearic acid, silicon dioxide, sodium stearyl fumarate, and talc powder.

[0023] In some embodiments, the wetting agent in Step 2 is water.

[0024] In some embodiments, the granulating liquid in Step 3 is atomized and added into the wet granulator in Step 1 through a peristaltic pump or a pressure tank; the total mixed granules in Step 6 are added into a high-speed tablet press for tableting.

[0025] In some embodiments, the drying temperature in Step 4 is 50 °C.

[0026] Advantages of the present invention:

[0027] The desmopressin acetate tablet composition provided by the present invention has inexpensive and easily available excipients. Neutral excipients are used to replace the acidic excipients in the prescription, changing the environmental pH value during the granulation process to be neutral, so that desmopressin acetate is not easily hydrolyzed to generate impurities. The preparation process and finished product storage of the formulation after replacing the excipients have better stability performance.

[0028] The preparation method of desmopressin acetate tablets provided by the present invention adopts the conventional wet granulation process, which has a simple process, a short process duration, and is easy to scale up production; water is used as a wetting agent, reducing the explosion risk and avoiding the residue of organic solvents; during the whole preparation process, desmopressin acetate tablets are prepared in a wet granulator first, and then transferred to a fluidized bed for drying, so that the material is in a high-temperature and high-humidity state for only 20 - 60 minutes, with a short duration, reducing the impurity content of desmopressin acetate tablets and having good stability. Detailed implementation manners

[0029] To enable those skilled in the art to understand the features and effects of the present invention, the following provides a general description and definition of the terms and phrases mentioned in the specification and claims. Unless otherwise specified, all technical and scientific terms used herein shall have the ordinary meaning understood by those skilled in the art regarding the present invention. In case of conflict, the definition in this specification shall prevail.

[0030] The theories or mechanisms described and disclosed herein, whether right or wrong, shall not limit the scope of the present invention in any way, that is, the content of the present invention can be implemented without being limited by any specific theory or mechanism.

[0031] In this article, all features defined in the form of numerical ranges or percentage ranges, such as numerical values, quantities, contents, and concentrations, are only for the sake of brevity and convenience. Accordingly, the description of numerical ranges or percentage ranges should be regarded as having covered and specifically disclosed all possible sub-ranges and individual values within the range (including integers and fractions).

[0032] In this article, for the sake of concise description, all possible combinations of all technical features in each embodiment or example are not described. Therefore, as long as there is no contradiction in the combination of these technical features, the technical features in each embodiment or example can be combined arbitrarily, and all possible combinations should be considered as the scope described in this specification.

[0033] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. In addition, it should be understood that after reading the content taught by the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present invention.

[0034] In the following examples, conventional instruments and equipment in the art are used. For the experimental methods without specific conditions noted in the following examples, they are generally carried out under conventional conditions or according to the conditions recommended by the manufacturer. In the following examples, various raw materials are used. Unless otherwise specified, commercially available products are used, and their specifications are the conventional specifications in the art. In the specification of the present invention and the following examples, unless otherwise specified, "%" represents weight percentage, "parts" represents weight parts, and the ratios represent weight.

[0035] The following further describes a desmopressin acetate tablet composition and its preparation method provided by the present invention in combination with specific examples.

[0036] Example 1: Preparation of Preparation 1

[0037] (1) Premix mannitol, microcrystalline cellulose, hydroxypropyl cellulose, and cross-linked carboxymethyl cellulose sodium using a high-shear wet granulator;

[0038] (2) Dissolve the desmopressin acetate raw material in the wetting agent water;

[0039] (3) Add the granulation liquid prepared in step (2) to the wet granulator for granulation, while stirring and shearing. The stirring speed is 280 rpm, the cutting speed is 1500 rpm, and the granulation time is 2 min;

[0040] (4) After sieving the granules prepared in step (3), transfer them to a fluidized bed for drying; the drying temperature is 50 °C, and the drying duration is 20 min;

[0041] (5) After sieving the dried granules obtained in step (4) through a granule screen, mix them evenly with the lubricant;

[0042] (6) Add the total mixed granules obtained in step (5) to a high-speed tableting machine for tableting.

[0043] Refer to the above preparation process and prepare Preparation 1 according to the prescription shown in Table 1.

[0044] Table 1 Formulation composition of Preparation 1

[0045] Component Mass (mg) / tablet Percentage (%) Desmopressin Acetate 0.1 0.05 Mannitol 116.9 58.45 Microcrystalline Cellulose 70 35 Hydroxypropyl Cellulose 6 3 Sodium Crosslinked Carboxymethylcellulose 6 3 Magnesium Stearate 1 0.5 Total 200 100

[0046] Example 2: Preparation of Preparation 2

[0047] (1) Premix mannitol, microcrystalline cellulose, hydroxypropyl methylcellulose, and sodium carboxymethyl starch using a high-shear wet granulator;

[0048] (2) Dissolve the desmopressin acetate raw material in the wetting agent water;

[0049] (3) Add the granulation liquid from step (2) to a wet granulator for granulation while stirring and shearing. The stirring speed is 280 rpm, the cutting speed is 1500 rpm, and the granulation time is 2 min.

[0050] (4) Screen the granules prepared in step (3) and transfer them to a fluidized bed for drying. The drying temperature is 50 °C and the drying duration is 30 min.

[0051] (5) Screen the dried granules obtained in step (4) and mix them evenly with a lubricant.

[0052] (6) Add the total mixed granules obtained in step (5) to a high-speed tablet press for tableting.

[0053] Prepare Preparation 2 according to the above preparation process and the prescription shown in Table 2.

[0054] Table 2 Formulation composition of Preparation 2

[0055] Component Mass (mg) / tablet Percentage (%) Desmopressin Acetate 0.2 0.1 Mannitol 116.9 58.45 Microcrystalline Cellulose 70 35 Hydroxypropyl Methylcellulose 6 3 Sodium Carboxymethyl Starch 6 3 Magnesium Stearate 0.9 0.45 Total 200 100

[0056] Example 3: Preparation of Preparation 3

[0057] (1) Premix mannitol, pregelatinized starch, hydroxypropyl cellulose, and cross-linked carboxymethyl cellulose sodium using a high-shear wet granulator.

[0058] (2) Dissolve desmopressin acetate API in the wetting agent water.

[0059] (3) Add the granulation liquid from step (2) to a wet granulator for granulation while stirring and shearing. The stirring speed is 280 rpm, the cutting speed is 1500 rpm, and the granulation time is 3 min.

[0060] (4) Screen the granules prepared in step (3) and transfer them to a fluidized bed for drying. The drying temperature is 50 °C and the drying duration is 25 min.

[0061] (5) Screen the dried granules obtained in step (4) and mix them evenly with a lubricant.

[0062] (6) Add the total mixed granules obtained in step (5) to a high-speed tablet press for tableting.

[0063] Prepare Preparation 3 according to the above preparation process and the prescription shown in Table 3.

[0064] Table 3 Formulation composition of Preparation 3

[0065] Component Mass (mg) / tablet Percentage (%) Desmopressin Acetate 0.1 0.05 Mannitol 112.9 56 Pregelatinized Starch 66 33 Hydroxypropyl Cellulose 10 5 Sodium Crosslinked Carboxymethylcellulose 9.9 4.95 Magnesium Stearate 2 1 Total 200 100

[0066] Example 4: Preparation of Preparation 4

[0067] (1) Premix mannitol, pregelatinized starch, hydroxypropyl cellulose, and low-substituted hydroxypropyl cellulose using a high-shear wet granulator;

[0068] (2) Dissolve desmopressin acetate API in the wetting agent water;

[0069] (3) Add the granulating liquid from step (2) to the wet granulator for granulation, while stirring and shearing simultaneously. The stirring speed is 280 rpm, the cutting speed is 1500 rpm, and the granulation time is 4 min;

[0070] (4) Screen the granules prepared in step (3) and transfer them to the fluidized bed for drying; the drying temperature is 40 °C, and the drying duration is 50 min;

[0071] (5) Screen the dried granules obtained in step (4) and mix them evenly with the lubricant;

[0072] (6) Add the total mixed granules obtained in step (5) to a high-speed tablet press for tableting.

[0073] Prepare Preparation 4 according to the above preparation process and the prescription shown in Table 4.

[0074] Table 4 Formulation composition of Preparation 4

[0075] Component Mass (mg) / tablet Percentage (%) Desmopressin Acetate 0.1 0.05 Mannitol 116.9 58.45 Pregelatinized Starch 70 35 Hydroxypropyl Cellulose 2 1 Low Substituted Hydroxypropyl Cellulose 10 5 Magnesium Stearate 1.0 0.5 Total 200 100

[0076] Example 5: Preparation of Preparation 5

[0077] (1) Premix mannitol, pregelatinized starch, hypromellose, and croscarmellose sodium using a high-shear wet granulator;

[0078] (2) Dissolve desmopressin acetate API in the wetting agent water;

[0079] (3) Add the granulating liquid from step (2) to the wet granulator for granulation, while stirring and shearing simultaneously. The stirring speed is 280 rpm, the cutting speed is 1500 rpm, and the granulation time is 2 min;

[0080] (4) Screen the granules prepared in step (3) and transfer them to the fluidized bed for drying; the drying temperature is 40 °C, and the drying duration is 60 min;

[0081] (5) Screen the dried granules obtained in step (4) and mix them evenly with the lubricant;

[0082] (6) Add the total mixed granules obtained in step (5) to a high-speed tablet press for tableting.

[0083] Prepare Preparation 5 according to the above preparation process and the prescription shown in Table 5.

[0084] Formulation Composition of Preparation 5

[0085] Component Mass (mg) / tablet Percentage (%) Desmopressin Acetate 0.1 0.05 Mannitol 116.9 58.45 Pregelatinized Starch 70 35 Hydroxypropyl Methylcellulose 10 5 Sodium Crosslinked Carboxymethylcellulose 2 1 Magnesium Stearate 1.0 0.5 Total 200 100

[0086] Example 6: Preparation of Preparation 6

[0087] (1) Premix mannitol, microcrystalline cellulose, hypromellose, and crospovidone using a high-shear wet granulator;

[0088] (2) Dissolve desmopressin acetate API in wetting agent water;

[0089] (3) Add the granulation liquid from step (2) to the wet granulator for granulation while performing stirring and shearing, with a stirring speed of 280 rpm, a cutting speed of 1500 rpm, and a granulation time of 2 min;

[0090] (4) Screen the granules prepared in step (3) and transfer them to a fluidized bed for drying; the drying temperature is 40 °C and the drying duration is 55 min;

[0091] (5) Screen the dried granules obtained in step (4) and mix them evenly with the lubricant;

[0092] (6) Add the total mixed granules obtained in step (5) to a high-speed tablet press for tableting.

[0093] Refer to the above preparation process and prepare Preparation 6 according to the prescription shown in Table 6.

[0094] Table 6 Formulation Composition of Preparation 6

[0095] Component Mass (mg) / tablet Percentage (%) Desmopressin Acetate 0.1 0.05 Mannitol 117.5 58.75 Microcrystalline Cellulose 70 35 Hydroxypropyl Methylcellulose 6 3 Crosslinked Povidone 6 3 Magnesium Stearate 0.4 0.2 Total 200 100

[0096] Comparative Example 1: Preparation of Preparation 7

[0097] (1) Premix lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, and croscarmellose sodium using a high-shear wet granulator;

[0098] (2) Dissolve desmopressin acetate API in wetting agent water;

[0099] (3) Add the granulation liquid from step (2) to the wet granulator for granulation while performing stirring and shearing, with a stirring speed of 280 rpm, a cutting speed of 1500 rpm, and a granulation time of 2 min;

[0100] (4) Screen the granules prepared in step (3) and transfer them to a fluidized bed for drying; the drying temperature is 50 °C and the drying duration is 20 min;

[0101] (5) Screen the dried granules obtained in step (4) and mix them evenly with the lubricant;

[0102] (6) Add the total mixed granules obtained in step (5) to a high-speed tableting machine for tableting.

[0103] Refer to the above preparation process and prepare Preparation 7 according to the prescription shown in Table 7.

[0104] Table 7 Formulation composition of Preparation 7

[0105]

[0106]

[0107] Comparative Example 2: Preparation of Preparation 8

[0108] (1) Premix mannitol, potato starch, hydroxypropyl cellulose, and cross-linked carboxymethyl cellulose sodium using a high-shear wet granulator;

[0109] (2) Dissolve the desmopressin acetate API in the wetting agent water;

[0110] (3) Add the granulation liquid prepared in step (2) to a wet granulator for granulation, while performing stirring and shearing. The stirring speed is 280 rpm, the cutting speed is 1500 rpm, and the granulation time is 2 min;

[0111] (4) Screen the granules prepared in step (3) and transfer them to a fluidized bed for drying; the drying temperature is 50 °C and the drying duration is 20 min;

[0112] (5) Screen the dried granules obtained in step (4) and mix them evenly with the lubricant;

[0113] (6) Add the total mixed granules obtained in step (5) to a high-speed tableting machine for tableting.

[0114] Refer to the above preparation process and prepare Preparation 8 according to the prescription shown in Table 8.

[0115] Table 8 Formulation composition of Preparation 8

[0116] Component Mass (mg) / tablet Percentage (%) Desmopressin Acetate 0.1 0.05 Mannitol 116.9 58.45 Potato Starch 70 35 Hydroxypropyl Cellulose 6 3 Sodium Crosslinked Carboxymethylcellulose 6 3 Magnesium Stearate 1 0.5 Total 200 100

[0117] Comparative Example 3: Preparation of Preparation 9

[0118] (1) Premix mannitol, microcrystalline cellulose, polyvinylpyrrolidone, and cross-linked carboxymethyl cellulose sodium using a high-shear wet granulator;

[0119] (2) Dissolve the desmopressin acetate API in the wetting agent water;

[0120] (3) Add the granulation liquid prepared in step (2) to a wet granulator for granulation, while performing stirring and shearing. The stirring speed is 280 rpm, the cutting speed is 1500 rpm, and the granulation time is 2 min;

[0121] (4) Granulate the particles prepared in step (3) and transfer them to a fluidized bed for drying; the drying temperature is 50 °C and the drying duration is 30 min;

[0122] (5) Granulate the dried particles obtained in step (4) through a granulator and mix them evenly with the lubricant;

[0123] (6) Add the total mixed particles obtained in step (5) to a high-speed tablet press for tableting.

[0124] The preparation 9 was prepared according to the above preparation process and the prescription shown in Table 9.

[0125] Table 9 Formulation composition of preparation 9

[0126] Component Mass (mg) / tablet Percentage (%) Desmopressin Acetate 0.1 0.05 Mannitol 116.9 58.45 Microcrystalline Cellulose 70 35 Povidone 6 3 Sodium Crosslinked Carboxymethylcellulose 6 3 Magnesium Stearate 1 0.5 Total 200 100

[0127] Comparative example 4: Preparation of preparation 10

[0128] (1) Premix lactose monohydrate, potato starch, hydroxypropyl cellulose, and cross-linked carboxymethyl cellulose sodium using a high-shear wet granulator;

[0129] (2) Dissolve the desmopressin acetate raw material in the wetting agent water;

[0130] (3) Add the granulation liquid prepared in step (2) to a wet granulator for granulation, and at the same time carry out stirring and shearing. The stirring speed is 280 rpm, the cutting speed is 1500 rpm, and the granulation time is 2 min;

[0131] (4) Granulate the particles prepared in step (3) and transfer them to a fluidized bed for drying; the drying temperature is 50 °C and the drying duration is 30 min;

[0132] (5) Granulate the dried particles obtained in step (4) through a granulator and mix them evenly with the lubricant;

[0133] (6) Add the total mixed particles obtained in step (5) to a high-speed tablet press for tableting.

[0134] The preparation 10 was prepared according to the above preparation process and the prescription shown in Table 10.

[0135] Table 10 Formulation composition of preparation 10

[0136] Component Mass (mg) / tablet Percentage (%) Desmopressin Acetate 0.1 0.05 Lactose Monohydrate 116.9 58.45 Potato Starch 70 35 Hydroxypropyl Cellulose 6 3 Sodium Crosslinked Carboxymethylcellulose 6 3 Magnesium Stearate 1 0.5 Total 200 100

[0137] Comparative example 5: Preparation of preparation 11

[0138] (1) Premix lactose monohydrate, microcrystalline cellulose, polyvinylpyrrolidone, and cross-linked carboxymethyl cellulose sodium using a high-shear wet granulator;

[0139] (2) Dissolve the desmopressin acetate bulk drug in the wetting agent water;

[0140] (3) Add the granulation liquid from step (2) to a wet granulator for granulation, while stirring and shearing. The stirring speed is 280 rpm, the cutting speed is 1500 rpm, and the granulation time is 2 min;

[0141] (4) Screen the granules prepared in step (3) and transfer them to a fluidized bed for drying; the drying temperature is 45 °C and the drying duration is 40 min;

[0142] (5) Screen the dried granules obtained in step (4) and mix them evenly with the lubricant;

[0143] (6) Add the total mixed granules obtained in step (5) to a high-speed tablet press for tableting.

[0144] Prepare preparation 11 according to the above preparation process and the prescription shown in Table 11.

[0145] Table 11 Formulation composition of preparation 11

[0146] Component Mass (mg) / tablet Percentage (%) Desmopressin Acetate 0.1 0.05 Lactose Monohydrate 116.9 58.45 Microcrystalline Cellulose 70 35 Povidone 6 3 Sodium Crosslinked Carboxymethylcellulose 6 3 Magnesium Stearate 1 0.5 Total 200 100

[0147] Comparative example 6: Preparation of preparation 12

[0148] (1) Premix mannitol, potato starch, polyvinylpyrrolidone, and cross-linked carboxymethyl cellulose sodium using a high-shear wet granulator;

[0149] (2) Dissolve the desmopressin acetate bulk drug in the wetting agent water;

[0150] (3) Add the granulation liquid from step (2) to a wet granulator for granulation, while stirring and shearing. The stirring speed is 280 rpm, the cutting speed is 1500 rpm, and the granulation time is 2 min;

[0151] (4) Screen the granules prepared in step (3) and transfer them to a fluidized bed for drying; the drying temperature is 45 °C and the drying duration is 40 min;

[0152] (5) Screen the dried granules obtained in step (4) and mix them evenly with the lubricant;

[0153] (6) Add the total mixed granules obtained in step (5) to a high-speed tablet press for tableting.

[0154] Prepare preparation 12 according to the above preparation process and the prescription shown in Table 12.

[0155] Table 12 Formulation composition of preparation 12

[0156] Component Mass (mg) / tablet Percentage (%) Desmopressin Acetate 0.1 0.05 Mannitol 116.9 58.45 Potato Starch 70 35 Povidone 6 3 Sodium Crosslinked Carboxymethylcellulose 6 3 Magnesium Stearate 1 0.5 Total 200 100

[0157] Experimental Example 1: Stability Study

[0158] The related substances of the wet granules and dry granules during the process of the preparations 1-12 obtained in Examples 1-6 and Comparative Examples 1-6 were detected. The preparations 1-12 obtained in Examples 1-6 and Comparative Examples 1-6 and the commercially available preparation Minirin (components and contents: active ingredient desmopressin acetate 0.05%, filler lactose monohydrate 61.97%, filler potato starch 36.78%, binder povidone 0.95% and lubricant magnesium stearate 0.25%) were subjected to stability study under accelerated conditions (40°C / 75% RH). After storage for 6 months, the changes in their related substances were investigated. The HPLC detection results of the wet granules are shown in Table 13, the HPLC detection results of the dry granules are shown in Table 14, and the HPLC detection results of the stability study are shown in Table 15.

[0159] Table 13 Research Data of Wet Granules

[0160]

[0161] Table 14 Research Data of Dry Granules

[0162]

[0163] Table 15 Research Data of Stability Study

[0164]

[0165] Among them, impurity 1 is the impurity generated by the hydrolysis of the raw material drug. The impurity content of the commercially available preparation Minirin is relatively high after storage for 6 months under accelerated conditions (40°C / 75% RH). From the results of Tables 13-15, it can be seen that compared with the commercially available preparation Minirin and the comparative preparation, the stability of the preparation obtained by the present invention is significantly improved, and the impurity content is significantly reduced.

[0166] Experimental Example 2: Dissolution Study

[0167] The preparations 1-12 were dissolved using the paddle method according to the requirements of the Chinese Pharmacopoeia. The preparations 1-12 and the commercially available preparation Minirin were placed in pH 4.5 acetate buffer (500 mL) and stirred at 37°C and a stirring speed of 75 rpm. After 5, 10, 15, 30, and 45 minutes, 10 mL of the sample was taken out, and the dissolution of the active ingredient was determined by HPLC. The results are shown in Table 16 below.

[0168] Table 16 Dissolution Data of Desmopressin Acetate in Samples

[0169] 5min 10min 15min 30min 45min Preparation 1 71 91 94 97 98 Preparation 2 71 90 94 96 98 Preparation 3 73 89 95 96 98 Preparation 4 72 91 95 98 99 Preparation 5 74 90 93 97 99 Preparation 6 72 90 95 96 98 Preparation 7 78 89 92 96 97 Preparation 8 75 90 93 96 98 Preparation 9 75 90 93 95 98 Preparation 10 74 91 94 95 97 Preparation 11 77 89 93 95 98 Preparation 12 76 89 92 96 99 Minirin 73 93 96 98 99

[0170] According to the data in the above table, it can be seen that under the condition of pH 4.5, within 45 minutes, the dissolution of Formulations 1 to 12 is basically the same as that of the commercially available preparation Minirin. That is, the dissolution rate of the sample of the preparation obtained in the present invention is consistent with that of the comparative preparation and Minirin.

[0171] Experimental Example 3: Evaluation of Bioavailability

[0172] Beagle dogs were used as experimental animals, and the dosing conditions were as follows:

[0173] Fasting period: The animals were not fed in the evening before dosing. Water and regular feed (SSNIFF hdH) were given at 1 hour and 4 hours after dosing, respectively.

[0174] Feeding period: 10 minutes before dosing, the animals received 50 g of high-fat diet (SSNIFF EF Dog FDA high-fat model, the diet has an energy value of 100 kcal and is composed of 15% protein, 25% carbohydrate and 50 - 60% fat). Then water and regular dog feed (SSNIFF hdH) were given at 1 hour and 4 hours after dosing, respectively.

[0175] Pretreatment with pentagastrin was carried out 0.5 hour before dosing. Pentagastrin was administered intramuscularly (6 μg / kg, 0.25 mL / kg) and the pH of the animals' stomachs was maintained between 2 and 3 to simulate the human state.

[0176] The treatment with the preparation prepared in the present invention was as follows:

[0177] Treatment 1: Formulation 1 tablets, fasting condition, oral route.

[0178] Treatment 2: Formulation 2 tablets, fasting condition, oral route.

[0179] Comparative Treatment 1: Minirin (0.1 mg specification), fasting condition, oral route.

[0180] Treatment 3: Formulation 1 tablets, feeding condition, oral route.

[0181] Treatment 4: Formulation 2 tablets, feeding condition, oral route.

[0182] Comparative Treatment 2: Minirin (0.1 mg specification), feeding condition, oral route.

[0183] Sampling and analysis:

[0184] Blood samples were collected in plastic tubes containing lithium heparin as an anticoagulant at the following sample collection times: before treatment and at 0 h, 0.5 h, 1 h, 1.33 h, 1.67 h, 2 h, 2.33 h, 2.67 h, 3 h, 3.5 h, 4 h, 4.5 h, 5 h, 6 h, 8 h, 10 h, 12 h, 14 h after administration of each treatment.

[0185] The plasma concentration of desmopressin acetate was determined by liquid chromatography tandem mass spectrometry (LC-MS / MS) using an exploratory analytical method, and the results are shown in Table 17.

[0186] Table 17 Pharmacokinetic parameters of desmopressin acetate (mean ± SD (CV%)) (n = 6 for each formulation)

[0187]

[0188] Among them, the pharmacokinetic parameters:

[0189] C max (ng / mL): corresponding to the observed maximum plasma concentration;

[0190] T max (h): corresponding to the observed time to obtain the maximum concentration;

[0191] AUC last : corresponding to the area under the curve or integral of the plasma concentration as a function of time t, calculated from t0 to the time corresponding to the final measurable concentration by the trapezoidal method;

[0192] AUC: corresponding to the area under the curve or integral of the plasma concentration as a function of the extrapolated time to infinity;

[0193] T 1 / 2z : the final elimination half-life.

[0194] From the results in Table 17, it can be seen that in the fasting and fed states, the observed C max and AUC of the desmopressin acetate tablets provided by the present invention are similar to the C max and AUC calculated for the commercially available Minirin, and the quality of the product and the sample bioavailability are consistent with those of the Minirin formulation.

[0195] Although the present invention has been disclosed above with preferred embodiments, it is not intended to limit the present invention. Any person familiar with this technology can make various modifications and alterations without departing from the spirit and scope of the present invention. Therefore, the protection scope of the present invention should be defined by the claims.

Claims

1. A desmopressin acetate tablet composition, characterized in that, The components and their contents of the composition are as follows by weight percentage: Desmopressin acetate as the active ingredient: 0.05% - 0.1%, filler as the neutral excipient: 89% - 95%, binder: 1% - 5%, disintegrant: 1% - 5%, and lubricant: 0.2% - 1.0%; The filler is one or more of mannitol, microcrystalline cellulose, pregelatinized starch, and corn starch; the binder is one or more of hypromellose, hydroxypropyl cellulose, ethyl cellulose, and sodium carboxymethyl cellulose; the disintegrant is one or more of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and sodium carboxymethyl starch; the lubricant is one or more of magnesium stearate, stearic acid, silica, sodium stearyl fumarate, and talc powder.

2. The desmopressin acetate tablet composition according to claim 1, characterized in that, The filler is a mixture of mannitol and microcrystalline cellulose; mannitol accounts for 45 - 75% of the components, and the microcrystalline cellulose accounts for 20 - 50% of the components.

3. The desmopressin acetate tablet composition according to claim 1, characterized in that, The binder is hydroxypropyl cellulose; hydroxypropyl cellulose accounts for 1% - 5% of the components.

4. The desmopressin acetate tablet composition according to claim 1, characterized in that, The disintegrant is croscarmellose sodium; croscarmellose sodium accounts for 1% - 5% of the components.

5. The desmopressin acetate tablet composition according to claim 1, characterized in that, The lubricant is magnesium stearate; magnesium stearate accounts for 0.2% - 1.0% of the components.

6. A method for preparing a desmopressin acetate tablet, characterized in that, Including: Step 1, add the filler, disintegrant, and binder into a wet granulator and mix evenly; Step 2, dissolve desmopressin acetate in a wetting agent; Step 3, add the granulating liquid prepared in Step 2 into the wet granulator in Step 1, add and mix simultaneously, and mix for another 2 - 4 min at room temperature after adding; Step 4, wet-screen the wet granules obtained in Step 3 through a screening machine, and then transfer them to a fluidized bed for drying, with the drying temperature of 40 - 50°C and the drying duration of 20 - 60 min; Step 5, screen the dried granules obtained in Step 4 through a screening machine and mix them evenly with the lubricant; Step 6, compress the total mixed granules obtained in Step 5 into tablets.

7. The method for preparing a desmopressin acetate tablet according to claim 6, characterized in that, By weight percentage: filler 89% - 95%, binder 1% - 5%, disintegrant 1% - 5%, and lubricant 0.2% - 1.0%; the filler is one or more of mannitol, microcrystalline cellulose, pregelatinized starch, and corn starch; the binder is one or more of hypromellose, hydroxypropyl cellulose, ethyl cellulose, and sodium carboxymethyl cellulose; the disintegrant is one or more of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and sodium carboxymethyl starch; the lubricant is one or more of magnesium stearate, stearic acid, silica, sodium stearyl fumarate, and talc powder.

8. The method for preparing a desmopressin acetate tablet according to claim 6, characterized in that, The wetting agent in Step 2 is water.

9. The method for preparing a desmopressin acetate tablet according to claim 6, characterized in that, In Step 3, the granulating liquid is atomized and added into the wet granulator in Step 1 through a peristaltic pump or a pressure tank; in Step 6, the total mixed granules are added into a high-speed tablet press for tableting.

10. The method for preparing a desmopressin acetate tablet according to claim 6, characterized in that, The drying temperature in Step 4 is 50°C.

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