A preparation method for controlling hyperphosphatemia

Abstract

The invention relates to the field of pharmaceutical preparations, in particular to the field of dry granulation technology, and specifically discloses a method for preparing a preparation composition for controlling hyperphosphatemia. The preparation is used for controlling hyperphosphatemia. The invention adopts reasonable preparation steps and preparation formulas. The method changes the raw material into dry granulation rather than wet granulation, reasonably distributes the use of various components in each step, adjusts the parameters of each preparation step, and improves the distribution of each particle size. Specifically, the main drug, microcrystalline cellulose KG802, sodium chloride, cross-linked polyvinylpyrrolidone, hydroxypropyl methylcellulose, stearate and other components are used, combined with specific mixing parameters such as roller pressure, roller gap, crushing speed, screen mesh number, and the remaining cross-linked polyvinylpyrrolidone and zinc stearate are added through secondary total mixing. On the basis of qualified disintegration, the tablet impurities and in vitro equilibrium test and in vitro kinetics, in vivo and in vitro phosphorus binding ability are better than the original preparation, thereby improving the utilization of the main drug.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical preparations, in particular to the field of dry granulation technology, and specifically discloses a method for preparing a preparation composition for controlling hyperphosphatemia. Background Art

[0002] Chronic kidney disease (CKD) is characterized by high prevalence, low awareness, poor prognosis and high medical costs. It is another disease that seriously endangers human health in addition to cardiovascular and cerebrovascular diseases, diabetes and malignant tumors. In recent years, the prevalence of CKD has increased year by year. The prevalence in the general population worldwide has reached 14.3%. A cross-sectional epidemiological survey in my country showed that the prevalence of CKD in people over 18 years old was 10.8%. In adults, a serum phosphorus concentration greater than 1.45 mmol / L is called hyperphosphatemia. Blood phosphorus management is an important part of improving the prognosis of CKD patients. Studies have shown that for every 1 mg / dL increase in blood phosphorus, the risk of death increases by 20%.

[0003] Sevelamer carbonate is a new type of calcium-free phosphate binder. It is a phosphate-binding cross-linked polymer that is not absorbed by the human body and does not contain metals or calcium. It carries multiple ammonium groups and is connected to the polymer backbone through a carbon atom. After oral administration of Sevelamer, the ammonium groups exist in the intestine in a protonated form, and bind to the phosphate groups in the gastrointestinal tract through ion exchange and hydrogen bonds to achieve the effect of reducing phosphorus. Sevelamer is not absorbed by the human body, has no risk of accumulation, and long-term use will not cause serious adverse reactions, with good safety. It can reduce its absorption by combining with phosphorus in the gastrointestinal tract. It is widely used clinically for the treatment of hyperphosphatemia in adult patients with chronic kidney disease who are undergoing dialysis treatment and hyperphosphatemia in adult patients with chronic kidney disease whose serum phosphorus is greater than or equal to 1.78 mmol / L but who are not undergoing dialysis. Compared with metal-containing phosphate binders such as aluminum hydroxide and calcium carbonate, sevelamer carbonate can effectively avoid the risks of elevated blood calcium and metal accumulation. Authoritative medical guidelines recommend sevelamer carbonate as a first-line treatment for hyperphosphatemia.

[0004] Sevelamer Carbonate Tablets, original product name: Novela ® , is a white to off-white oval film-coated tablet, with a recommended starting dose of 0.8g or 1.6g each time. On July 20, 2021, Sanofi announced that the China National Medical Products Administration officially approved the application for the expansion of the indication of Novela, that is, it is approved for the control of hyperphosphatemia in adult patients with chronic kidney disease with serum phosphorus greater than or equal to 1.78 mmol / L but not undergoing dialysis. On August 15, 2023, Sevelamer Carbonate Tablets (trademark: Wansuwen) developed and produced by Amneal and exclusively commercialized by Fosun Pharma ®) obtains drug registration approval from the National Medical Products Administration (NMPA), which is deemed to have passed the generic drug consistency evaluation.

[0005] The original formulation process of Sevelamer Carbonate Tablets is wet granulation, but Sevelamer and its salts have special properties. They will expand in volume when exposed to water. Based on relevant research results, the volume of the raw materials can be expanded by about three times after absorbing water. Therefore, before wet granulation, the amount of raw materials and auxiliary materials added is only 20%~35% of the reasonable filling range of the pot, which limits the possibility of further batch expansion. The compressibility of the raw material itself is poor, so its hardness, friability, and disintegration time are considered as important evaluations in its key quality attributes and quality standards and are included in the evaluation scope.

[0006] Chinese patent CN102908325 A proposes to add a certain weight ratio of pharmaceutical excipients cross-linked polyvinylpyrrolidone and silicon dioxide, and use wet granulation to obtain a carbonated sevelamer tablet with a hardness of more than 140N and a friability of less than 1%. However, the disintegration stability of the patented product is poor, and its disintegration time will increase with the increase of storage time. Chinese patent CN 116549409A proposes to spray-dry the carbonated sevelamer raw material, filler and solvent after homogenization, and then mix them evenly with disintegrants and lubricants, and then press them into tablets. The hardness of the plain tablets prepared by this preparation method is above 500 N, and the plain tablets can be coated normally without the need for a special coating process, but the disintegration time of the prepared coated tablets is generally about 7 to 10 min, which is too long and inconsistent with the original research. Chinese patent CN 107397734 A obtains a product with better stability by adding a certain proportion of lubricants polyethylene glycol 4000 and behenic acid glyceryl esters, and the disintegration time is improved. However, the friability of the product described in the patent example is still greater than 0.4%. Chinese patent CN 117224497 A proposes to add triethyl citrate to the core component of sevelamer carbonate tablets to improve the compressibility and disintegration stability of sevelamer carbonate, but the patent also states that when the weight ratio of sevelamer carbonate to triethyl citrate reaches 800:100, the prepared plain tablet has a hardness of 357N and a friability of 0.12%; the disintegration time of the coated tablet is less than 3.5 minutes, and the disintegration time is less than 5 minutes after 6 months.

[0007] The batch size of sevelamer carbonate is limited due to its volume expansion during wet granulation. The traditional solution is to solve the batch problem by merging sub-batches and mixing them together. The wet granulation of sub-batches is still time-consuming and labor-intensive. Even after changing the wet preparation method to a dry preparation method, the requirements of titratable amine and phosphate binding, phosphate binding kinetics, and phosphate binding in vitro equilibrium need to be met. Therefore, an optimized preparation process for sevelamer carbonate tablets is required. Summary of the invention

[0008] In view of the above-mentioned prior art, the object of the present invention is to provide a method for preparing a preparation composition for controlling hyperphosphatemia. The preparation composition for controlling hyperphosphatemia prepared by the present invention has similar quality attributes to the original preparation (wet preparation).

[0009] To achieve the above object, the present invention adopts the following technical solutions:

[0010] The first aspect of the present invention provides a method for preparing a preparation composition for controlling hyperphosphatemia, comprising the following steps:

[0011] S1: 780-860 parts by weight of sevelamer are mixed with 15-17 parts by weight of crospovidone and 33-35 parts by weight of hypromellose K100LV, and then 20-22 parts by weight of sodium chloride or monosodium citrate and 169-171 parts by weight of microcrystalline cellulose KG802 or cellulose lactose T80 are added and mixed;

[0012] S2: The mixed material is screened through a sieve with a hole diameter of 0.9~1.1mm according to a feeding speed of 14~16rpm, a roller pressure of 44~46bar, a roller gap of 0.9~1.1mm, and a crushing speed of 7~9rpm;

[0013] S3: after mixing the granules granulated in step S2 with 16-18 parts by weight of cross-linked polyvinylpyrrolidone or sodium starch glycolate, 1.8-2.2 parts by weight of stearate are added, and mixed again;

[0014] S4: tabletting the mixture of step S3 to obtain plain tablets.

[0015] In some specific embodiments of the first aspect of the present invention, sodium chloride and microcrystalline cellulose KG802 are added 14 to 16 minutes after the sevelamer, crospovidone and hypromellose are mixed in step S1.

[0016] In some specific embodiments of the first aspect of the present invention, the substance input in step S1 is sevelamer carbonate or sevelamer hydrochloride.

[0017] In some specific embodiments of the first aspect of the present invention, the mixing rate of step S3 is 15-20 rpm.

[0018] In some specific embodiments of the first aspect of the present invention, after adding stearate in step S3, mixing is continued for 2 to 4 minutes.

[0019] In some specific embodiments of the first aspect of the present invention, the tableting in step S4 is performed using an elliptical punch with a long diameter of 19-21 mm and a short diameter of 9-11 mm.

[0020] In some specific embodiments of the first aspect of the present invention, the hardness control range of the blank sheet in step S4 is 250~320N.

[0021] In some specific embodiments of the first aspect of the present invention, the method further comprises applying atomized film coating to the plain tablet.

[0022] In some specific embodiments of the first aspect of the present invention, the atomized film coating conditions are as follows: an inlet air temperature of 45-65°C, a material temperature of 38-40°C, a peristaltic pump speed of 8-10 rpm, and an atomization pressure of 0.3-0.4 MPa.

[0023] In some specific embodiments of the first aspect of the present invention, the mass ratio of the plain tablet to the film coating is (14.3~15.0):1.

[0024] The experimental materials used in the examples of the present invention but not specifically described are all conventional experimental materials in the art and can be purchased through commercial channels.

[0025] Beneficial effects of the present invention:

[0026] 1. The present invention adopts a dry granulation process, avoids the use of solvents, increases the use of a neutral regulator, sodium chloride, and adjusts the dry granulation process so that the total mixed granules after dry granulation and the total mixed granules after wet granulation have similar particle size distributions, and the disintegration test, titratable amine and test are the same or slightly better than the prior art.

[0027] 2. When taking multiple drugs, these drugs may affect gastric acid secretion and thus change the pH value of the gastrointestinal tract. By simulating the phosphate binding kinetics at different time points of acid treatment / acid environment with a pH of 4.0 and 7.0 in the body, the present invention has a good effect on the absorption of phosphate under different environments (pH 4.0, 7.0 acid treatment / acid environment). After taking the drug, the absorption capacity can be quickly improved to the functional level. Under the premise that the phosphate binding rate meets the requirements, the absorption capacity of phosphate fluctuates less at different time points. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 : Comparison of the total mixed particle distribution diagrams of the wet preparation and dry preparation used in the prescriptions of Example 1 and Example 2. DETAILED DESCRIPTION

[0029] In order to enable those skilled in the art to more clearly understand the technical solution of the present application, the technical solution of the present application will be described in detail below in conjunction with specific embodiments. It should be noted that the following detailed descriptions are all illustrative and are intended to provide further explanation of the present application. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those generally understood by those of ordinary skill in the art to which the present application belongs.

[0030] The preparation composition for controlling hyperphosphatemia of the present invention is prepared by five steps:

[0031] (1) Premixing: Mix the main drug with disintegrant and binder for 15 minutes, then add neutral regulator and filler and mix for 5 minutes;

[0032] (2) Dry granulation: The premixed materials are dry granulated at a feeding speed of 15-20 rpm, a roller pressure of 45-60 bar, a roller gap of 1.0-1.2 mm, a crushing speed of 8-10 rpm, and a screen mesh of 1.0 mm-1.2 mm;

[0033] (3) Total mixing: Add the dry granulated granules and the remaining amount of disintegrant to the total mixing equipment and mix at a mixing speed of 15-20 rpm for 10-13 min. Add the prescribed amount of lubricant and mix for 3 min at the same mixing speed.

[0034] (4) Tablet pressing: Use an elliptical punch with a long diameter of 20 mm and a short diameter of 10 mm. The tablet weight should be in the range of 95% to 105% of the theoretical tablet weight. The hardness should be controlled in the range of 250 to 320 N.

[0035] (5) Coating: Prepare a 9-11% solution of the film coating premix; coat the plain tablets prepared in step (4) to prepare a preparation composition for controlling hyperphosphatemia. The specific conditions of the coating treatment are: inlet air temperature of 45-65°C, material temperature of 38-42°C, peristaltic pump speed of 8-10rpm, and atomization pressure of 0.3-0.4MPa.

[0036] Embodiment 1:

[0037] (1) Premixing: Mix the main drug with cross-linked polyvinylpyrrolidone and hypromellose K100LV for 15 minutes, then add sodium chloride and microcrystalline cellulose KG802 and mix for 5 minutes;

[0038] (2) Dry granulation: The premixed materials were dry granulated at a feed rate of 15 rpm, a roller pressure of 45 bar, a roller gap of 1.0 mm, a crushing speed of 8 rpm, and a screen mesh of 1.0 mm.

[0039] (3) Total mixing: The granules after dry granulation and the remaining cross-linked polyvinylpyrrolidone were added to the total mixing equipment and mixed at a mixing speed of 15 rpm for 10 min; then zinc stearate was added and mixed at a mixing speed of 15 rpm for 3 min.

[0040] (4) Tablet pressing: Use an elliptical punch with a long diameter of 20 mm and a short diameter of 10 mm. The tablet weight should be within the range of 95% to 105% of the theoretical tablet weight of 1060 mg. The hardness should be controlled within the range of 250 to 320 N, or 350 to 580 N.

[0041] (5) Coating: Prepare a 10% solution of the film coating premix; coat the plain tablets prepared in step (4) to prepare a preparation composition for controlling hyperphosphatemia. The specific conditions of the coating treatment are: inlet air temperature of 45-65°C, material temperature of 38-40°C, peristaltic pump speed of 8-10rpm, and atomization pressure of 0.3-0.4MPa.

[0042] According to the formula in Table 1, the homemade preparation (dry method) was obtained by following steps (1) to (5).

[0043] Table 1 Prescription information used in Example 1

[0044] Embodiment 2:

[0045] According to the actual commercial application of the present invention, the prescription can be expanded to a specification of 1600 mg according to the proportion, and through the adjustment of relevant proportions and replacement of materials, the prescription information is as follows:

[0046] Table 2 Prescription information used in Example 2

[0047] (1) Premixing: Mix the main drug with cross-linked polyvinylpyrrolidone and hypromellose K100LV for 15 minutes, then add cellulose lactose T80 and monosodium citrate and mix for 5 minutes;

[0048] (2) Dry granulation: The premixed materials were dry granulated at a feed rate of 20 rpm, a roller pressure of 60 bar, a roller gap of 1.2 mm, a crushing speed of 10 rpm, and a screen mesh of 1.0 mm.

[0049] (3) Total mixing: The granules after dry granulation and the remaining sodium carboxymethyl starch are added to the total mixing equipment and mixed at a mixing speed of 20 rpm for 13 min; then zinc stearate is added and mixed at a mixing speed of 20 rpm for 3 min;

[0050] (4) Tablet pressing: Use an elliptical punch with a long diameter of 20 mm and a short diameter of 10 mm. The tablet weight should be in the range of 97%-103% of the theoretical tablet weight of 2120 mg. The hardness should be controlled in the range of 350-580 N.

[0051] (5) Coating: Prepare a 10% solution of the film coating premix; coat the plain tablets prepared in step (4) to prepare a preparation composition for controlling hyperphosphatemia. The specific conditions for the coating treatment are: inlet air temperature 45-65°C, material temperature 38-40°C, peristaltic pump speed 8-10rpm, and atomization pressure: 0.3-0.4MPa.

[0052] According to the formula in Table 2, the homemade preparation (dry method) was obtained by following steps (1) to (5).

[0053] Comparative Example 1:

[0054] The difference between Comparative Example 1 and Example 1 is that the disintegrant, binder, filler and total disintegrant lubricant in the premix are replaced by the following table, and the weight of the materials is kept unchanged to prepare Groups 1 to 7:

[0055] Table 3 Replacement table of components of homemade preparation (dry method) in Example 1

[0056] Comparative Example 2:

[0057] The difference between Comparative Example 2 and Example 1 is that the feeding speed, roller pressure, roller gap, crushing speed, and screen mesh number are different in the dry granulation step:

[0058] Table 4 Parameter substitution table for the preparation steps of the homemade preparation (dry method) in Example 1

[0059] Comparative Example 3:

[0060] The difference between Comparative Example 3 and Example 1 is that 33 mg of cross-linked polyvinylpyrrolidone is added in the premixing step, and no cross-linked polyvinylpyrrolidone is added in the total mixing step. The rest is the same. Comparative Example 3 is Group 13.

[0061] Example 3: Performance test comparison

[0062] The total mixed particle distribution test was carried out on the homemade preparations (dry method) and homemade preparations (wet method) of Examples 1 and 2, and the results were as follows: Figure 1 .

[0063] Among them, the homemade preparation (wet method) of prescription A in Example 1 is made by wet granulation using the existing industrial method according to the prescription in Table 1, and the homemade preparation (wet method) of prescription A-1 in Example 2 is made by wet granulation using the existing industrial method according to the prescription in Table 2; the reference preparation (original drug) uses the commercially available original drug as the reference preparation;

[0064] Table 5 Disintegration test

[0065] Table 6 Comparison of titratable amine and phosphate binding capacity

[0066] Table 7 Results of investigation on key substances of active drug raw materials, reference preparations (original drugs) and homemade preparations (dry method)

[0067] Example 4: In vitro equilibrium test and in vitro kinetic binding study test:

[0068] The in vitro equilibrium test and in vitro kinetic binding study test were performed on the preparation of Example 1 using the design in Table 8:

[0069] Table 8 In vitro equilibrium binding studies and in vitro kinetic binding studies

[0070] Table 9 Summary of in vitro phosphate binding balance at different concentrations of homemade preparation (dry method) and reference preparation (original drug) in Example 1 (N=6)

[0071] Table 10 Summary of phosphate binding kinetics at different time points for the homemade preparation (dry method) and the reference preparation (original drug) of Example 1 (2 mM) (N=6)

[0072] Table 11 Summary of phosphate binding kinetics at different time points of homemade preparations (dry method) in Example 1 (60 mM) (N=6)

[0073] Example 5: In vitro kinetic binding comparison test of groups 1 to 13:

[0074] The design in Table 8 was used to conduct in vitro kinetic binding study tests on tablets in Groups 1 to 13, respectively. The test conditions were pH 4.0 acid treatment, and Table 12 was obtained:

[0075] Table 12 Summary of phosphate binding kinetics of the preparation compositions of Group 1 to Group 13 at different time points (2 mM) (N=6)

[0076] The above description is only the preferred embodiment of the present application and is not intended to limit the present application. For those skilled in the art, the present application may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A method for preparing a preparation composition for controlling hyperphosphatemia, characterized in that: The following steps are involved: S1: 780-860 parts by weight of sevelamer are mixed with 15-17 parts by weight of crospovidone and 33-35 parts by weight of hypromellose K100LV, and then 20-22 parts by weight of sodium chloride or monosodium citrate and 169-171 parts by weight of microcrystalline cellulose KG802 or cellulose lactose T80 are added and mixed; S2: The mixed material is screened through a sieve with a hole diameter of 0.9~1.1mm according to a feeding speed of 14~16rpm, a roller pressure of 44~46bar, a roller gap of 0.9~1.1mm, and a crushing speed of 7~9rpm; S3: after mixing the granules granulated in step S2 with 16-18 parts by weight of cross-linked polyvinylpyrrolidone or sodium starch glycolate, 1.8-2.2 parts by weight of stearate are added, and mixed again; S4: tableting the mixture from step S3 to obtain plain tablets; S5: The plain tablets prepared in step S4 are coated with Opadry Complete Film Coating System. The specific conditions of the coating treatment are: inlet air temperature 45-65°C, material temperature 38-42°C, peristaltic pump speed 8-10rpm, atomization pressure: 0.3-0.4MPa, and the mass ratio of the plain tablets to the film coating is 20:

1.

2. The method for preparing the formulation composition according to claim 1, characterized in that: In step S1, after mixing sevelamer, crospovidone and hypromellose K100LV for 14-16 minutes, sodium chloride and microcrystalline cellulose KG802 are added.

3. The method for preparing the formulation composition according to claim 1, characterized in that: In the step S1, sevelamer carbonate or sevelamer hydrochloride is added.

4. The method for preparing the formulation composition according to claim 1, characterized in that: The mixing rate of the S3 step is 15-20 rpm.

5. The method for preparing the formulation composition according to claim 1, characterized in that: After adding stearate in step S3, continue mixing for 2 to 4 minutes.

6. The method for preparing the formulation composition according to claim 1, characterized in that: The tableting in step S4 is performed using an elliptical punch with a long diameter of 19-21 mm and a short diameter of 9-11 mm.

7. The method for preparing the formulation composition according to claim 1, characterized in that: The hardness control range of the blank sheet in step S4 is 250~320N.

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