CN113304116B

CN113304116B - Tablet containing minodronic acid and preparation method thereof

Info

Publication number: CN113304116B
Application number: CN202110501309.9A
Authority: CN
Inventors: 圣晨; 张慧; 王华娟
Original assignee: Nanjing Healthnice Pharmaceutical Co ltd; Nanjing Yinuo Medicine Technology Co ltd; Nanjing Healthnice Pharmaceutical Technology Co ltd
Current assignee: Nanjing Healthnice Pharmaceutical Co ltd; Nanjing Yinuo Medicine Technology Co ltd; Nanjing Healthnice Pharmaceutical Technology Co ltd
Priority date: 2021-05-08
Filing date: 2021-05-08
Publication date: 2022-08-02
Anticipated expiration: 2041-05-08
Also published as: CN113304116A

Abstract

The invention relates to a minodronate-containing tablet and a preparation method thereof, wherein the tablet or tablet core is prepared from the following components in parts by mass: 50-100 parts of active component minodronic acid, 205-215 parts of diluent, 5-10 parts of internal disintegrating agent, 10-15 parts of adhesive, 6-21 parts of external disintegrating agent and 3-5 parts of lubricant. In the process of fluidized bed granulation, the dosage and the grain diameter of microcrystalline cellulose of an external disintegrant and parameter conditions in the granulation process are controlled by selecting the specific auxiliary materials and the proportion among the auxiliary materials, so that the dissolution rate of large-size minodronic acid tablets is improved, the problem of sticking of the tablets is effectively solved, and the tablet has the advantages of high dissolution rate, no sticking, good compression formability, good uniformity, high stability and the like.

Description

Tablet containing minodronic acid and preparation method thereof

Technical Field

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a minodronic acid-containing tablet and a preparation method thereof.

Background

Osteoporosis is a systemic, metabolic disease of the skeletal system characterized by decreased bone mass, destruction of bone microarchitecture, increased bone fragility, decreased bone strength, and increased risk of fracture. With the aging of the population, osteoporosis seriously threatens the health of middle-aged and elderly people, especially middle-aged and elderly women, and the prevalence rate of osteoporosis of women is 3 times that of men. It is estimated that by 2020, the number of osteoporosis patients will increase to 2.866 million people, hip fracture will reach 163.82 million people, and osteoporosis patients will increase to 5.333 million people in 2050. In china, with the increase in life expectancy and the increasing population of the elderly over 70 years of age, the burden of osteoporosis and fractures will increase dramatically, with the osteoporosis-related fractures increasing by 1-fold by 2035 years. Osteoporosis and related fractures are important factors in increasing mortality and morbidity in postmenopausal women, whose residual life after a more severe fracture occurs is shorter than after breast cancer. Postmenopausal bone mass decreases rapidly, e.g., early in the menopause, with an average of about 3% reduction in bone density at the distal forearm per year, 2-3% reduction in bone density per year in 3 years post-menopause in the spine and femoral neck, and more rapidly in women early in the menopause (pre-age 45), with an average 3-4% reduction in bone density per year.

Bisphosphonates effectively inhibit bone resorption and have been shown to be effective in preventing vertebral and hip fractures. The bisphosphonate is the most important preparation for resisting bone resorption at present, has a structure similar to that of pyrophosphate which is an endogenous bone metabolism regulator, and changes a P-O-P bond in pyrophosphate which is easily hydrolyzed in an acid environment or inactivated by being destroyed by pyrophosphatase into a P-C-P structure, so that the bisphosphonate has stable properties in vivo. The compound can inhibit bone resorption at low dose.

Minodronic acid is a third-generation aza-aryl bisphosphonate derivative, has bone resorption resisting activity 100-1000 times higher than that of pamidronate, and can antagonize osteolysis caused by myeloma and tumor. In non-clinical trials, the product shows good bone resorption resistance, and inhibition of bone density and bone strength reduction with lower dosages than existing bisphosphonate drugs.

Minodronic acid (Minodronic acid) tablets were co-developed by nippon philippinarum and astella japan pharmaceutical co-production, and were approved at 1 mg/tablet on the market 1 month in 2009, and were taken once a day. In 2011, 9 months, 50 mg/tablet is marketed in Japan and is taken once a month.

The action part: it is believed that minodronate hydrate accumulates in bone, is released by acid during bone resorption, and is resorbed by osteoclasts to exert a bone resorption inhibitory effect.

The action mechanism is as follows: minodronate hydrate is believed to reduce bone turnover by inhibiting farnesyl pyrophosphate (FPP) synthase in osteoclasts and inhibiting the bone resorption function of osteoclasts.

Therefore, the development purpose of the product mainly comes from the characteristics of raw materials, the solubility of the raw materials is poor, a long-acting tablet with the specification of 50mg (1 time every 4 weeks) is prepared according to the action mechanism of minodronic acid, the aim of the preparation development is to obtain a film coated tablet which can be quickly dissolved out, a preparation method of a minodronic acid tablet capable of improving the dissolution and absorption rate of a medicament is needed, the 50mg minodronic acid tablet can be ensured to be effective for a long time while the medicament dosage is improved, the medicament taking frequency of a patient is reduced, and the compliance of the patient is enhanced.

Chinese patent application CN103070874A discloses a minodronate tablet and a preparation method thereof, which is characterized in that minodronate and hydrophilic auxiliary materials are uniformly mixed and then put into grinding equipment to be ground to prepare minodronate co-ground material, other auxiliary materials are added, ethanol is used as a wetting agent to be granulated and tabletted. However, the pretreatment process of raw and auxiliary materials is complex and energy consumption is large.

The minodronate tablet disclosed by Chinese patent application CN102144982A comprises a minodronate solid dispersion, a diluent, a disintegrating agent and a lubricant, wherein the minodronate solid dispersion consists of minodronate, polyethylene glycol and an additive, the polyethylene glycol is heated to a molten state, the additive is slowly added and stirred to be dissolved, minodronate is added and stirred to be completely dissolved, then the minodronate is cooled, placed for 18-24 hours, crushed and sieved to prepare the minodronate solid dispersion, and then the diluent, the disintegrating agent and the lubricant are added and mixed, and finally the minodronate tablet is prepared by tabletting. However, the preparation process is complex, long in time, high in energy consumption, harsh in process, easy to make mistakes in workshop production and difficult to realize industrial production.

Chinese patent application CN104771379A discloses a minodronic acid tablet and its preparation method, wherein minodronic acid and hydroxypropyl methylcellulose are dissolved in sodium hydroxide aqueous solution, and the solution is coated on a blank tablet prepared by mixing and granulating crospovidone, microcrystalline cellulose and magnesium stearate. However, the coating process is strict and irregular, and the raw material dissolution is a problem for large-size minodronic acid tablets, and the coating efficiency is not fixed, so that excessive feeding is required, the feeding amount is uncertain, and the content of the finished product has a large risk.

Disclosure of Invention

The invention aims to provide a minodronic acid-containing tablet based on the prior art, which has the advantages of high dissolution rate, no sticking, no need of special auxiliary materials, simple preparation method and suitability for industrial production.

Another object of the present invention is to provide a method for preparing the minodronic acid-containing tablet.

The technical scheme of the invention is as follows:

a minodronic acid tablet is prepared from the following components in parts by mass: 50-100 parts of active component minodronic acid, 205-215 parts of diluent, 5-10 parts of internal disintegrating agent, 10-15 parts of adhesive, 6-21 parts of external disintegrating agent and 3-5 parts of lubricant; in the preparation process, the active component minodronic acid, the diluent and the internal disintegrating agent are firstly placed in a fluidized bed to be uniformly mixed, and then are granulated with the adhesive water solution, and the obtained granules are mixed with the external disintegrating agent and the lubricant to be tabletted.

For the tablet of the present invention, it comprises minodronic acid as an active ingredient and auxiliary materials. Wherein the adjuvants comprise diluent, internal disintegrating agent, binder, external disintegrating agent, and lubricant. The diluent is one or more of mannitol, microcrystalline cellulose, corn starch or lactose, preferably mannitol. The internal disintegrating agent is croscarmellose sodium, and the adhesive is hydroxypropyl cellulose with the model L; the added disintegrating agent is microcrystalline cellulose with the average grain diameter of 50-100 mu m; the lubricant is magnesium stearate.

In a preferred embodiment, the minodronate tablet comprises a core and a coating: wherein the tablet core is prepared from the following components in parts by mass: 50-100 parts of active component minodronic acid, 211 parts of diluent, 6 parts of croscarmellose sodium, 13.5 parts of hydroxypropyl cellulose, 6-21 parts of microcrystalline cellulose and 4.5 parts of magnesium stearate.

In a more preferred embodiment, the minodronate tablet comprises a core and a coating: wherein the tablet core is prepared from the following components in parts by mass: active ingredients of 50 parts of minodronic acid, 211 parts of mannitol (diluent), 6 parts of croscarmellose sodium, 13.5 parts of hydroxypropyl cellulose, 6-21 parts of microcrystalline cellulose and 4.5 parts of magnesium stearate.

For example, the minodronate tablet comprises a core and a coating: wherein the tablet core is prepared from the following components in parts by mass: active components of 50 parts of minodronic acid, 211 parts of mannitol (diluent), 6 parts of croscarmellose sodium, 13.5 parts of hydroxypropyl cellulose, 6 parts of microcrystalline cellulose and 4.5 parts of magnesium stearate.

For example, the minodronate tablet comprises a core and a coating: wherein the tablet core is prepared from the following components in parts by mass: active components of 50 parts of minodronic acid, 211 parts of mannitol (diluent), 6 parts of croscarmellose sodium, 13.5 parts of hydroxypropyl cellulose, 15 parts of microcrystalline cellulose and 4.5 parts of magnesium stearate.

For example, the minodronate tablet or tablet core is prepared from the following components in parts by mass: active component minodronic acid 50 parts, mannitol (diluent) 211 parts, croscarmellose sodium 6 parts, hydroxypropyl cellulose 13.5 parts, microcrystalline cellulose 21 parts and magnesium stearate 4.5 parts.

In a more preferred embodiment, the minodronate tablet comprises a core and a coating: wherein the tablet core is prepared from the following components in parts by mass: active ingredients of 50 parts of minodronic acid, 211 parts of lactose (diluent), 6 parts of croscarmellose sodium, 13.5 parts of hydroxypropyl cellulose, 6-21 parts of microcrystalline cellulose and 4.5 parts of magnesium stearate.

In a more preferred embodiment, the minodronate tablet comprises a core and a coating: wherein the tablet core is prepared from the following components in parts by mass: active ingredients of the composition comprise 50 parts of minodronic acid, 121 parts of mannitol (diluent), 90 parts of microcrystalline cellulose (diluent), 6 parts of croscarmellose sodium, 13.5 parts of hydroxypropyl cellulose, 6-21 parts of microcrystalline cellulose and 4.5 parts of magnesium stearate.

In a more preferred embodiment, the minodronate tablet comprises a core and a coating: wherein the tablet core is prepared from the following components in parts by mass: active ingredients of 50 parts of minodronic acid, 151 parts of lactose (diluent), 60 parts of corn starch (diluent), 6 parts of croscarmellose sodium, 13.5 parts of hydroxypropyl cellulose, 6-21 parts of microcrystalline cellulose and 4.5 parts of magnesium stearate.

In a more preferred embodiment, the minodronate tablet comprises a core and a coating: wherein the tablet core is prepared from the following components in parts by mass: active ingredients of 100 parts of minodronic acid, 211 parts of mannitol (diluent), 6 parts of croscarmellose sodium, 13.5 parts of hydroxypropyl cellulose, 6-21 parts of microcrystalline cellulose and 4.5 parts of magnesium stearate.

The invention also provides a preparation method of the minodronic acid tablet, which comprises the following steps:

1) pretreatment: sieving the active components and adjuvants;

2) and (3) granulating: putting active component minodronic acid, diluent and internal disintegrating agent into a fluidized bed, mixing uniformly, and granulating with an adhesive aqueous solution;

3) mixing, tabletting and coating: and (3) uniformly mixing the granules obtained in the step (2) with an external disintegrating agent and a lubricating agent, and tabletting and coating.

In a preferable scheme, in the step (1), the particle size of D90 in the active component minodronic acid is 1-20 μm; sieving the active components with a sieve of 80-120 meshes, preferably 100 meshes; and (3) sieving the auxiliary materials by a sieve of 40-80 meshes, preferably 60 meshes.

For the tablet of the present invention, it comprises minodronic acid as an active ingredient and auxiliary materials. Wherein the adjuvants comprise diluent, internal disintegrating agent, binder, external disintegrating agent and lubricant. The diluent is one or more of mannitol, microcrystalline cellulose, corn starch or lactose, preferably mannitol. The internal disintegrating agent is croscarmellose sodium, and the adhesive is hydroxypropyl cellulose with the model L; the added disintegrating agent is microcrystalline cellulose with the average grain diameter of 50-100 mu m; the lubricant is magnesium stearate.

In the step (2), the active component minodronic acid, the diluent and the internal disintegrating agent are placed in a fluidized bed to be uniformly mixed, and are granulated with an adhesive aqueous solution, wherein the adhesive aqueous solution is an aqueous solution prepared by dissolving an adhesive (hydroxypropyl cellulose, type L) in water and diluting the adhesive (hydroxypropyl cellulose, type L) to prepare the adhesive, and the mass content of the adhesive (hydroxypropyl cellulose, type L) in the adhesive aqueous solution can be, but is not limited to, 5%, 7%, 10%, 12% or 15%.

Further, in the step (2), in the granulation in the fluidized bed, the parameter conditions were set as follows: the granulation process comprises air volume of 16-30Hz, atomization pressure of 0.1-0.3mpa, spraying binder solution at 40-45 deg.C, top spraying granulation at spraying speed of 4-8rpm, and controlling granulation temperature at 35-40 deg.C.

Preferably, in the step (2), in the granulation in the fluidized bed, the parameter conditions are set as follows: the granulation process comprises air flow of 20Hz, atomization pressure of 0.2mpa, spraying binder solution at 40-45 deg.C, and granulating at a speed of 4-8rpm and a temperature of 35-40 deg.C.

Further, in the step (2), in the fluidized bed granulation process, granulating through a 24-40-mesh sieve, and drying at the drying temperature of 50-70 ℃; then, sieving the granules by a 40-mesh sieve and drying the granules; preferably, the drying temperature is 65 ℃ and the water content is controlled to be 2-4% during drying.

In the step (3), during tabletting, the weight of the tablet is controlled to be 290-310mg, and the hardness is controlled to be 80-100N; coating with gastric soluble film coating material, and controlling the coating weight increase by 2.5-3.5%.

The fluidized bed granulation, namely one-step granulation, is mainly characterized in that 3 steps of mixing, granulating and drying of the conventional wet granulation are completed in a closed container at one time. The one-step granulation can keep the medicine powder in a suspended fluidized state under the action of airflow from bottom to top, the adhesive solution is sprayed into the fluidizing chamber from the upper part or the lower part, the powder is agglomerated into particles, and dry mixing, wet mixing, stirring, particle forming and drying of the materials are completed in the same fluidized bed equipment, so that a large number of operation links are reduced, and the production cost is saved. The one-step granulation can also ensure that the preparation process is carried out in a sealed environment, thereby not only preventing the pollution of the outside to the medicine, but also reducing the contact chance of operators with the medicine and auxiliary materials with irritation or toxicity. In the process of fluidized bed granulation, the dosage and the particle size of the microcrystalline cellulose of the externally added disintegrating agent and the parameter conditions in the granulation process are controlled by selecting the specific auxiliary materials and the proportion among the auxiliary materials, and under the condition of matching other conditions, the prepared granules have the advantages of uniform force, good fluidity and compression formability, high dissolution rate, no sticking and impact, uniform distribution of the medicine with lower content in the formula in the granules, production time saving and the like, and the problem of low dissolution rate caused by static electricity, aggregation and adsorption after the raw auxiliary materials are crushed is solved.

For the present invention, it is necessary to control the amount and particle size of microcrystalline cellulose as an external disintegrant. The sticking problem of the tablet can be effectively solved by controlling the addition amount of the external disintegrant microcrystalline cellulose in the formula, and the sticking phenomenon of the prepared tablet occurs due to the too small dosage of the external disintegrant microcrystalline cellulose; the excessive consumption of the microcrystalline cellulose of the external disintegrating agent can wrap the disintegrated particles, so that the dissolution contact area of the particles is reduced, and the later-period dissolution rate is influenced. When the active component minodronic acid is 50-100 parts by mass, 6-21 parts by mass of the additionally added disintegrant microcrystalline cellulose needs to be controlled, wherein the best effect is achieved when the weight is controlled to be 15 parts.

When the microcrystalline cellulose is adopted as an external disintegrating agent, the grain diameter of the microcrystalline cellulose also needs to be strictly controlled, when the grain diameter of the microcrystalline cellulose of the external disintegrating agent is fine, the prepared tablet has no luster on the tablet surface, and insoluble precipitate with larger volume is formed after disintegration, so that the particles which are not completely dissolved out during disintegration are wrapped, and the later-period dissolution rate is influenced; when the microcrystalline cellulose with large particle size is used as an external disintegrating agent, the disintegrating effect is reduced, and the dissolution is incomplete. Therefore, when the microcrystalline cellulose is selected as the external disintegrating agent, the average particle size is controlled to be 50-100 μm, wherein the effect is best when the particle size is controlled to be 65 μm.

By adopting the technical scheme of the invention, the advantages are as follows:

according to the minodronic acid tablet prepared by the method, in the process of fluidized bed granulation, the specific auxiliary materials and the proportion of the auxiliary materials are selected, the dosage and the particle size of microcrystalline cellulose of an externally added disintegrating agent and the parameter conditions in the granulation process are controlled, the dissolution rate of large-size minodronic acid tablets is improved, the problem of sticking of the tablets is effectively solved, and the minodronic acid tablet has the advantages of high dissolution rate, no sticking, good compression formability, good uniformity, high stability and the like.

The preparation method of the minodronic acid tablet overcomes the sticking problem commonly existing in the preparation process of large-size minodronic acid tablets, and the selected auxiliary materials are also conventional when the tablet is prepared, so that the requirement on production equipment is low, the production energy consumption is reduced, the production steps are simplified, and the preparation method is suitable for large-scale industrial production.

Drawings

FIG. 1 is a comparison of dissolution curves of different methods for preparing minodronate tablets;

FIG. 2 is a comparison of dissolution curves of microcrystalline cellulose for different particle sizes.

Detailed Description

The tablet and the process for preparing the tablet according to the present invention will be further illustrated by the following examples in conjunction with the drawings, which are not intended to limit the present invention in any way.

The dosage of the raw materials and the auxiliary materials of the minodronic acid tablets (1000 tablets) prepared by different diluents is shown in the table 1.

TABLE 1 formulation of minodronic acid tablets

Example 1:

1000 minodronate tablets were prepared according to the formulation in table 1, the specific preparation method being as follows:

1) pretreatment: active component minodronic acid (D90: 1-20 μm) is sieved by a 100-mesh sieve for later use; sieving mannitol (diluent), croscarmellose sodium (internal disintegrating agent), microcrystalline cellulose (external disintegrating agent) and magnesium stearate (lubricant) with 60 mesh sieve; hydroxypropyl cellulose (type L) is dissolved in water and prepared into 10% aqueous solution as adhesive solution for use.

2) And (3) granulating: 50g of minodronic acid, 211g of mannitol and 6g of croscarmellose sodium are placed in a fluidized bed and mixed for 10min under the condition of an air flow of 20 HZ. Granulation was then carried out in a fluidized bed with the parameters set to: granulating at 24Hz and 0.2mpa under atomizing pressure, spraying binder solution at 40-45 deg.C, spraying at 4-8rpm, controlling granulating temperature at 35-40 deg.C, sieving with 40 mesh sieve, granulating, drying at 65 deg.C and controlling water content at 2-4%; sieving with 40 mesh sieve, drying, and grading.

3) Mixing: mixing 15g microcrystalline cellulose (average particle size 65 μm) and the dry granules obtained in step (2) in a hopper mixer at 15rpm for 10 minutes, adding 4.5g magnesium stearate and mixing for 10 minutes;

4) tabletting and coating: the tablet weight is controlled to be 290 mg and the hardness is controlled to be 80-100N, and a gastric soluble film coating material is adopted for coating, so that the coating weight is controlled to be increased by 2.5-3.5%.

Example 2:

1) pretreatment: active component minodronic acid (D90: 1-20 μm) is sieved by a 100-mesh sieve for later use; sieving lactose (diluent), croscarmellose sodium (with disintegrant), microcrystalline cellulose (with disintegrant) and magnesium stearate (lubricant) with 60 mesh sieve; hydroxypropyl cellulose (model L) is dissolved in water and prepared into 10% aqueous solution as adhesive solution for later use.

2) And (3) granulating: 50g of minodronic acid, 211g of lactose and 6g of croscarmellose sodium are placed in a fluidized bed and mixed for 10min under the condition of an air flow of 20 HZ. Granulation was then carried out in a fluidized bed with the parameters set to: granulating at 24Hz and 0.2mpa under atomizing pressure, spraying binder solution at 40-45 deg.C, spraying at 4-8rpm, controlling granulating temperature at 35-40 deg.C, sieving with 40 mesh sieve, granulating, drying at 65 deg.C and controlling water content at 2-4%; sieving with 40 mesh sieve, drying, and grading.

3) Mixing: 15g of microcrystalline cellulose (mean particle size 65 μm) and the dry granules obtained in step (2) were mixed in a hopper mixer at 15rpm for 10 minutes, followed by addition of 4.5g of magnesium stearate and mixing for 10 minutes;

Example 3:

1) pretreatment: active component minodronic acid (D90: 1-20 μm) is sieved by a 100-mesh sieve for later use; sieving mannitol (diluent), croscarmellose sodium (internal disintegrating agent), microcrystalline cellulose (diluent and external disintegrating agent) and magnesium stearate (lubricant) with 60 mesh sieve; hydroxypropyl cellulose (model L) is dissolved in water and prepared into 10% aqueous solution as adhesive solution for later use.

2) And (3) granulating: 50g of minodronic acid, 121g of mannitol, 90g of microcrystalline cellulose and 6g of croscarmellose sodium are placed in a fluidized bed and mixed for 10min under the condition of an air volume of 20 HZ. Granulation was then carried out in a fluidized bed with the parameters set to: granulating at air flow rate of 24Hz and atomization pressure of 0.2mpa, spraying binder solution at 40-45 deg.C, spraying at spraying speed of 4-8rpm, controlling granulation temperature at 35-40 deg.C, sieving with 40 mesh sieve, granulating, drying at drying temperature of 65 deg.C and water content of 2-4%; sieving with 40 mesh sieve, drying, and grading.

Example 4:

1) pretreatment: active component minodronic acid (D90: 1-20 μm) is sieved by a 100-mesh sieve for later use; sieving lactose (diluent), corn starch (diluent), croscarmellose sodium (internal disintegrating agent), microcrystalline cellulose (external disintegrating agent) and magnesium stearate (lubricant) with 60 mesh sieve; hydroxypropyl cellulose (model L) is dissolved in water and prepared into 10% aqueous solution as adhesive solution for later use.

2) And (3) granulating: 50g of minodronic acid, 151g of lactose, 60g of corn starch and 6g of croscarmellose sodium are placed in a fluidized bed and mixed for 10min under the condition of an air flow of 20 HZ. Granulation was then carried out in a fluidized bed with the parameters set to: granulating at air flow rate of 24Hz and atomization pressure of 0.2mpa, spraying binder solution at 40-45 deg.C, spraying at spraying speed of 4-8rpm, controlling granulation temperature at 35-40 deg.C, sieving with 40 mesh sieve, granulating, drying at drying temperature of 65 deg.C and water content of 2-4%; sieving with 40 mesh sieve, drying, and grading.

Example 5:

1) pretreatment: active component minodronic acid (D90: 1-20 μm) is sieved by a 100-mesh sieve for later use; sieving mannitol (diluent), croscarmellose sodium (internal disintegrating agent), microcrystalline cellulose (external disintegrating agent) and magnesium stearate (lubricant) with 60 mesh sieve; hydroxypropyl cellulose (model L) is dissolved in water and prepared into 10% aqueous solution as adhesive solution for later use.

2) And (3) granulating: 100g of minodronic acid, 211 of mannitol and 6g of croscarmellose sodium are placed in a fluidized bed and mixed for 10min under the condition of air volume of 20 HZ. Granulation was then carried out in a fluidized bed with the parameters set to: granulating at air flow rate of 24Hz and atomization pressure of 0.2mpa, spraying binder solution at 40-45 deg.C, spraying at spraying speed of 4-8rpm, controlling granulation temperature at 35-40 deg.C, sieving with 40 mesh sieve, granulating, drying at drying temperature of 65 deg.C and water content of 2-4%; sieving with 40 mesh sieve, drying, and grading.

4) tabletting and coating: controlling the tablet weight to be 340-360mg and the hardness to be 80-100N, and coating by adopting a gastric-soluble film coating material, wherein the coating weight is controlled to be increased by 2.5-3.5%.

Comparative example 1:

1) pretreatment: active component minodronic acid (D90: 1-20 μm) is sieved by a 100-mesh sieve for later use; mannitol (diluent), croscarmellose sodium (internal disintegrating agent), microcrystalline cellulose (diluent + external disintegrating agent) and magnesium stearate (lubricant) are sieved by a 60-mesh sieve for later use.

2) And (3) granulating: 50g of minodronic acid, 121g of mannitol, 90g of microcrystalline cellulose, 13.5g of hydroxypropyl cellulose (model L) and 6g of croscarmellose sodium are placed in a high-shear wet granulation pot, stirred, and mixed for 10min at the rotation speed of 500rpm and the rotation speed of a cutter of 1000 rpm. After uniformly mixing, adding 50g of purified water under the conditions that the rotating speed is 500rpm and the rotating speed of a cutter is 1500rpm, sieving by a 18-mesh sieve for granulation, and then drying, wherein the drying temperature is 65 ℃, and the water content is controlled to be 2-4%; sieving with 20 mesh sieve, and drying.

Comparative example 2:

1) pretreatment: active component minodronic acid (D90: 1-20 μm) is sieved by a 100-mesh sieve for later use; lactose (diluent), corn starch (diluent), croscarmellose sodium (internal disintegrating agent), microcrystalline cellulose (external disintegrating agent) and magnesium stearate (lubricant) are sieved by a 60-mesh sieve for later use.

2) And (3) granulating: 50g of minodronic acid, 151g of lactose, 60g of corn starch, 13.5g of hydroxypropyl cellulose (type L) and 6g of croscarmellose sodium are placed in a high-shear wet granulation pot, stirred, and mixed for 10min at the rotation speed of 500rpm and the rotation speed of a cutter of 1000 rpm. After uniformly mixing, adding 60g of purified water under the conditions that the rotating speed is 500rpm and the rotating speed of a cutter is 1500rpm, sieving by a 18-mesh sieve for granulation, and then drying, wherein the drying temperature is 65 ℃, and the water content is controlled to be 2-4%; sieving with 20 mesh sieve, and drying.

Comparative example 3: the formula for preparing 1000 minodronate tablets is as follows:

the preparation method comprises the following steps:

1) co-grinding: referring to the co-grinding method disclosed in chinese patent CN103070874A, the specific steps are as follows: weighing 50g of active component minodronic acid (D90: 1-20 mu m) and 211g of mannitol, uniformly mixing, and then placing the mixture into a ball mill for ball milling for 30min to prepare a minodronic acid co-ground substance, wherein the average particle size of the minodronic acid co-ground substance is controlled to be 20 mu m;

2) granulating: to the minodronate co-grind was added 13.5g of hydroxypropyl cellulose (type L) and placed in a high shear wet granulation kettle, the agitation was turned on and the mixing was carried out for 10min at 500rpm and 1000rpm of the cutter. After uniformly mixing, adding a proper amount of 70% ethanol solution to wet under the conditions that the rotating speed is 500rpm and the rotating speed of a cutter is 1500rpm to prepare a soft material, sieving with a 20-mesh sieve to granulate, drying the obtained wet granules in an oven, wherein the drying temperature is 65 ℃, and the water content is controlled to be 2-4%; sieving with 20 mesh sieve, and drying.

3) Mixing: mixing 15g of microcrystalline cellulose (mean particle size 65 μm), 6g of croscarmellose sodium and the dry granules obtained in step (2) in a hopper mixer at 15rpm for 10 minutes, adding 4.5g of magnesium stearate and mixing for 10 minutes;

4) tabletting and coating: the tablet weight is controlled to be 290 mg and the hardness is controlled to be 80-100N, a gastric soluble film coating material is adopted for coating, and the weight gain of the coating is controlled to be 2.5-3.5%

Comparative example 4a formulation for 1000 minodronate tablets was prepared as follows:

the preparation process comprises the following steps:

1) and preparing a solid dispersion: referring to the preparation method of the dispersion disclosed in Chinese patent CN102144982A, the details are as follows: heating 750g of polyethylene glycol 6000 to 80 ℃, keeping the temperature until the polyethylene glycol 6000 is completely melted, slowly adding 35g of polyvinyl alcohol, stirring until the polyvinyl alcohol is dissolved, adding 50g of minodronic acid (D90: 1-20 mu m) serving as an active component, stirring until the minodronic acid is completely dissolved, continuing stirring, cooling to 0-4 ℃, standing for 20 hours to form a solid fragile object, crushing, and sieving with a 60-mesh sieve to obtain a minodronic acid solid dispersion;

2) weighing 1000g of microcrystalline cellulose (with the average particle size of 65 mu m), 2000g of lactose, 350g of croscarmellose sodium and the minodronic acid solid dispersion prepared in the step (1), placing the materials into a hopper mixer, mixing the materials for 20 minutes at the speed of 15rpm, adding 40g of magnesium stearate, and continuing to mix the materials for 10 minutes;

3) tabletting and coating: tabletting to make each tablet contain 50mg of minodronic acid, and coating with gastric soluble film coating material to control the coating weight increase of 2.5-3.5%.

Comparative example 5 a formulation for 1000 minodronate tablets was prepared as follows:

the preparation process comprises the following steps:

1) referring to the preparation method disclosed in the Chinese patent CN104771379A, the method comprises the following steps: uniformly mixing 500g of sodium carboxymethyl starch, 3000g of microcrystalline cellulose and 50g of magnesium stearate, and tabletting to obtain 50mg of minodronic acid in each tablet;

2) 50g of the active ingredient minodronic acid (D90: 1-20 μm), 150g hydroxypropyl methyl cellulose in a proper amount of sodium hydroxide aqueous solution, and coating the solution on the compressed tablets.

Dissolution curve measurement method:

the method comprises the following steps: basket method, dissolution medium: 0.1M hydrochloric acid solution, dissolution medium: 900ml, rotation speed: 100 rpm, sampling time point: 5. sampling for 10min, 15 min, 20 min, 30min and 45min, taking 10ml of solution (simultaneously adding solvent with the same volume), filtering with water film, and taking appropriate amount of subsequent filtrate for dilution to obtain test solution.

Control solution: taking about 11mg of minodronic acid reference substance, precisely weighing, placing in a 100ml measuring flask, adding a dissolution medium, ultrasonically dissolving, diluting to scale, and shaking uniformly. Precisely transferring 2.5ml of the solution, placing the solution in a 10ml measuring flask, adding a dissolution medium to dilute the solution to a scale, and shaking up the solution to serve as a reference solution.

The determination method comprises the following steps: UV method, wavelength 282 nm.

The results of the key quality attributes and 0.1M hydrochloric acid dissolution curves of the minodronic acid tablets prepared in the comparative examples and comparative examples are shown in tables 2 and 3.

TABLE 2 Key Properties of minodronate tablets prepared in examples and comparative examples

As can be seen from table 2, the tablets obtained by the comparative fluidized bed granulation (examples 1 to 5) and the high shear granulation (comparative examples 1 to 2) have no problem in the difference in tablet weight and the content uniformity, but the high shear granulation has a higher granulation strength and a part of hard particles cannot be dissolved out, and the dissolution rate of the obtained tablets is lower than that of the fluidized bed granulation in 30 min. The tablets prepared with the solid dispersion (comparative example 4) are clearly not mixed uniformly and there is a great risk of content uniformity in the finished product. The minodronic acid raw and auxiliary materials are dissolved, coated and applied (comparative example 5), the content is unqualified due to neglect of reduction of coating efficiency, excessive feeding is needed, and the tablet weight difference is larger and larger as the weight of the coated and applied medicine is increased.

TABLE 3 dissolution curve results of minodronic acid tablets prepared in examples and comparative examples

As can be seen from Table 3, when the minodronate tablets are prepared by adopting a fluidized bed granulation method (examples 1 to 5) for different types of fillers, the prepared granules are loose and uniform, the dissolution rate is very fast and uniform, and the dissolution rate is fastest compared with other granulation methods. A high-shear granulation method (comparative examples 1-2) is adopted, and due to the fact that the granulation strength is high, a part of hard particles can be generated, and the dissolution of the end point cannot be realized; the dissolution rate of the minodronic acid tablet prepared by the co-grinding technology (comparative example 3) is improved to a certain extent, but the problem that hard particles cannot be dissolved at the end point after high-shear granulation is still solved; the solid dispersion (comparative example 4) had the problems of layering of fine particles and large dissolution RSD, and the intra-batch difference was significant; the content of finished products of coating and medicine application (comparative example 5) is too low, raw materials are added for coating according to theoretical amount, the content of the final finished products is obviously unqualified, excessive feeding is needed, and the requirement on the coating process is strict.

The fluidized bed granulation method used in the invention has the advantages of uniform and loose granules, improved dissolution rate, no preparation process difficulty, low amplification difficulty and low energy consumption.

In addition, in order to improve the dissolution rate of the minodronic acid tablets, the unexpected discovery in the search of comparing different types of externally added disintegrants shows that the dosage and the particle size of externally added microcrystalline cellulose are controlled, the disintegration is accelerated, the dissolution rate is improved, and meanwhile, the tablet sticking and punching can be obviously improved, so that the dosage and the particle size of the microcrystalline cellulose are studied in detail.

The dosage of the raw and auxiliary materials of the minodronic acid tablets (1000 tablets) prepared by different additional disintegrants and particle sizes is shown in Table 4.

TABLE 4 formulation of minodronic acid tablets

Example 6:

1000 minodronate tablets were prepared according to the formulation in table 4, the specific preparation method being as follows:

2) And (3) granulating: 50g of minodronic acid, 211g of mannitol and 6g of croscarmellose sodium are placed in a fluidized bed and mixed for 10min under the condition of an air flow of 20 HZ. Granulation was then carried out in a fluidized bed with the parameters set to: granulating at air flow rate of 24Hz and atomization pressure of 0.2mpa, spraying binder solution at material temperature of 40-45 deg.C, spraying at spraying speed of 4-8rpm, controlling granulation temperature at 35-40 deg.C, sieving with 40 mesh sieve, granulating, drying the obtained wet granules at drying temperature of 65 deg.C, and controlling water content at 2-4%; sieving with 40 mesh sieve, drying, and grading.

3) Mixing: mixing 6g microcrystalline cellulose (mean particle size 65 μm) and the dry granules obtained in step (2) in a hopper mixer at 15rpm for 10 minutes, adding 4.5g magnesium stearate and mixing for 10 minutes;

4) tabletting and coating: controlling the tablet weight to be 280-300mg and the hardness to be 80-100N, and coating by adopting a gastric-soluble film coating material, wherein the weight of the coating is controlled to be increased by 2.5-3.5%.

Example 7:

3) Mixing: 21g of microcrystalline cellulose (mean particle size 65 μm) and the dry granules obtained in step (2) were mixed in a hopper mixer at 15rpm for 10 minutes, and 4.5g of magnesium stearate was added and mixed for 10 minutes;

4) tabletting and coating: the tablet weight is controlled to be 295-315mg, the hardness is controlled to be 80-100N, and a gastric soluble film coating material is adopted for coating, so that the weight of the coating is controlled to be increased by 2.5-3.5%.

Example 8:

3) Mixing: mixing 21g microcrystalline cellulose (average particle size 100 μm) and the dry granules obtained in step (2) in a hopper mixer at 15rpm for 10 minutes, adding 4.5g magnesium stearate and mixing for 10 minutes;

Comparative example 6:

3) Mixing: 3g of microcrystalline cellulose (mean particle size 65 μm) and the dry granules obtained in step (2) were mixed in a hopper mixer at 15rpm for 10 minutes, and 4.5g of magnesium stearate was added and mixed for 10 minutes;

Comparative example 7:

3) Mixing: mixing 45g microcrystalline cellulose (average particle size 65 μm) and the dry granules obtained in step (2) in a hopper mixer at 15rpm for 10 minutes, adding 4.5g magnesium stearate and mixing for 10 minutes;

4) tabletting and coating: the tablet weight is controlled to be 320-340mg, the hardness is controlled to be 80-100N, and a gastric soluble film coating material is adopted for coating, so that the coating weight is controlled to be increased by 2.5-3.5%.

Comparative example 8:

1) pretreatment: active component minodronic acid (D90: 1-20 μm) is sieved by a 100-mesh sieve for later use; sieving mannitol (diluent), croscarmellose sodium (internal disintegrating agent), sodium carboxymethyl starch (external disintegrating agent) and magnesium stearate (lubricant) with 60 mesh sieve; hydroxypropyl cellulose (model L) is dissolved in water and prepared into 10% aqueous solution as adhesive solution for later use.

3) Mixing: 21g of sodium carboxymethyl starch (mean particle size 65 μm) and the dry granules obtained in step (2) were mixed in a hopper mixer at 15rpm for 10 minutes, and 4.5g of magnesium stearate was added and mixed for 10 minutes;

Comparative example 9:

1) pretreatment: active component minodronic acid (D90: 1-20 μm) is sieved by a 100-mesh sieve for later use; sieving mannitol (diluent), croscarmellose sodium (internal disintegrating agent), crospovidone (external disintegrating agent) and magnesium stearate (lubricant) with 60 mesh sieve; hydroxypropyl cellulose (model L) is dissolved in water and prepared into 10% aqueous solution as adhesive solution for later use.

3) Mixing: mixing 21g crospovidone (average particle size 65 μm) and the dry granules obtained in step (2) in a hopper mixer at 15rpm for 10 minutes, adding 4.5g magnesium stearate and mixing for 10 minutes;

Comparative example 10:

3) Mixing: mixing 21g microcrystalline cellulose (average particle size 25 μm) and the dry granules obtained in step (2) in a hopper mixer at 15rpm for 10 minutes, adding 4.5g magnesium stearate and mixing for 10 minutes;

Comparative example 11:

3) Mixing: mixing 21g microcrystalline cellulose (average particle size 150 μm) and the dry granules obtained in step (2) in a hopper mixer at 15rpm for 10 minutes, adding 4.5g magnesium stearate and mixing for 10 minutes;

The results of checking the key quality attributes of the minodronate tablets prepared in the comparative examples and comparative examples are shown in table 5 below.

TABLE 5 results of minodronic acid tablets prepared in examples and comparative examples

In Table 5, as can be seen from a comparison of the tablets prepared in examples 6 to 8 and comparative examples 6 to 7, the sticking problem of the tablets can be effectively solved by controlling the addition amount of microcrystalline cellulose as an external disintegrant, but the amount of microcrystalline cellulose to be used is controlled to 6 to 21mg, i.e., 2 to 7%, preferably 5%, i.e., 15 mg. For example, in comparative example 6, the microcrystalline cellulose was used in an excessively small amount, and the resulting tablet exhibited a sticking phenomenon; in comparative example 7, the use of an excessive amount of microcrystalline cellulose wrapped the disintegrated particles, which resulted in a decrease in the dissolution contact area of the particles and an influence on the dissolution rate at the later stage.

Example 7 and comparative examples 8-9 it can be seen that the use of sodium carboxymethyl starch and crospovidone instead of microcrystalline cellulose as an additional disintegrant does not solve the sticking problem that occurs during the manufacturing process of tablets.

Examples 7 to 8 and comparative examples 10 to 11 show that when microcrystalline cellulose is used as an external disintegrant, the particle size thereof needs to be strictly controlled, and from comparative example 10, when microcrystalline cellulose is used, the tablet surface of the tablet is matt, and insoluble precipitates with large volume are formed after disintegration, so that the particles which are not completely dissolved during disintegration are wrapped, and the later-stage dissolution rate is affected; as can be seen from comparative example 11, the use of microcrystalline cellulose having a large particle size as an external disintegrant reduced the disintegrating effect and resulted in incomplete dissolution. Therefore, when the microcrystalline cellulose is selected as the external disintegrating agent, the average particle size is controlled to be 50-100 μm.

The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: modifications of the technical solutions described in the foregoing embodiments are still possible, or some technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. The minodronic acid tablet is characterized in that the tablet or a tablet core is prepared from the following components in parts by mass: 50-100 parts of active component minodronic acid, 211 parts of diluent, 6 parts of internal disintegrating agent, 13.5 parts of adhesive, 6-21 parts of external disintegrating agent and 4.5 parts of lubricant; in the preparation process, the active component minodronic acid, the diluent and the internal disintegrating agent are placed in a fluidized bed and uniformly mixed, and are granulated with the aqueous solution of the adhesive, and then the obtained granules are mixed with the external disintegrating agent and the lubricant for tabletting; the internal disintegrating agent is croscarmellose sodium, and the adhesive is hydroxypropyl cellulose; the external disintegrating agent is microcrystalline cellulose, and the average particle size is 65-100 mu m; the lubricant is magnesium stearate; the diluent is 211 parts of mannitol, 211 parts of lactose, 121 parts of mannitol, 90 parts of microcrystalline cellulose, 151 parts of lactose and 60 parts of corn starch.

2. The minodronate tablet according to claim 1, wherein the diluent is mannitol; the particle size of D90 in the minodronic acid is 1-20 mu m.

3. The process for preparing minodronate tablets according to claim 1, characterized in that it comprises the following steps:

1) pretreatment: sieving the active components and adjuvants;

4. The process for the preparation of minodronate tablets according to claim 3, characterized in that it comprises the following steps: in the step (1), the particle size of D90 in the active component minodronic acid is 1-20 μm; sieving the active components with a sieve of 80-120 meshes; and (5) sieving the auxiliary materials by a sieve of 40-80 meshes.

5. The process for the preparation of minodronate tablets according to claim 4, characterized in that it comprises the following steps: in step (1), the active ingredient is passed through a 100 mesh screen.

6. The process for the preparation of minodronate tablets according to claim 4, characterized in that it comprises the following steps: in step (1), the adjuvants are sieved with a 60-mesh sieve.

7. The process for the preparation of minodronate tablets according to claim 3, characterized in that it comprises the following steps: in step (2), the diluent is mannitol; the mass content of the adhesive in the adhesive aqueous solution is 5-15%.

8. The process for preparing minodronate tablets according to claim 7, wherein the binder is present in the aqueous binder solution in an amount of 10% by weight.

9. The process for the preparation of minodronate tablets according to claim 3, characterized in that it comprises the following steps: in the step (2), when granulating in the fluidized bed, the parameter conditions are set as follows: the granulation process comprises air volume of 16-30Hz, atomization pressure of 0.1-0.3mpa, spraying binder solution at 40-45 deg.C, top spraying granulation at spraying speed of 4-8rpm, and controlling granulation temperature at 35-40 deg.C.

10. The process for the preparation of minodronate tablets according to claim 9, characterized in that it comprises the following steps: in the step (2), the mixture is sieved by a 24-40 mesh sieve, granulated and dried, wherein the drying temperature is 50-70 ℃; then, the mixture was sieved through a 40-mesh sieve, dried and granulated.

11. The process for the preparation of minodronate tablets according to claim 9, characterized in that it comprises the following steps: in the step (2), during drying, the drying temperature is 65 ℃, and the water content is controlled to be 2-4%.

12. The process for the preparation of minodronate tablets according to claim 3, characterized in that it comprises the following steps: in the step (3), during tabletting, the weight of the tablet is controlled to be 290-310mg, and the hardness is controlled to be 80-100N; coating with gastric soluble film coating material, and controlling the coating weight increase by 2.5-3.5%.