CN109464411B - Thyroid tablet produced by directly tabletting whole powder and preparation process thereof - Google Patents

Thyroid tablet produced by directly tabletting whole powder and preparation process thereof Download PDF

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CN109464411B
CN109464411B CN201710821025.1A CN201710821025A CN109464411B CN 109464411 B CN109464411 B CN 109464411B CN 201710821025 A CN201710821025 A CN 201710821025A CN 109464411 B CN109464411 B CN 109464411B
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周卫
丁宇
李娜
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China Pharmaceutical University
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Abstract

The invention belongs to the technical field of medicinal preparations, relates to a thyroid tablet produced by directly tabletting whole powder and a preparation process thereof, and particularly relates to synergistic application of calcium hydrogen phosphate for assisting in optimizing the property of thyroid raw material powder and a freeze-drying auxiliary crushing technology. The particle size of the thyroid gland mixed crushed material prepared by the invention is more than 98 percent and is less than 250 mu m, the thyroid gland mixed crushed material is not easy to be aggregated, and the thyroid gland mixed crushed material is uniformly mixed with other auxiliary materials; thyroid powder T3、T4The RSD content is less than or equal to 4 percent; the repose angle of the mixed powder is less than 35 degrees, and the requirement of direct tabletting of the powder is met; thyroid slice T3And T4The content uniformity A +2.2S is less than or equal to 20, each tablet is disintegrated within 15min, and the disintegration time difference is smaller (RSD is less than or equal to 5%). The invention effectively solves the problems that the thyroid gland raw material is not easy to crush and is not uniformly mixed with auxiliary materials, optimizes the crushing effect of the thyroid gland raw material, improves the powder property of the thyroid gland raw material, and greatly improves the T-shaped thyroid tablets3、T4Content uniformity of (d).

Description

Thyroid tablet produced by directly tabletting whole powder and preparation process thereof
The technical field is as follows:
the invention belongs to the technical field of medicinal preparations, relates to a thyroid tablet produced by directly tabletting whole powder and a preparation process thereof, and particularly relates to a thyroid powder capable of being directly pressed by powder prepared by the synergistic application of calcium hydrogen phosphate for assisting in optimizing the property effect of thyroid raw material powder and a freeze-drying and auxiliary crushing technology.
Background art:
thyroid hormone has a very important influence on the growth, development and metabolic level of a human body. In recent years, the incidence of diseases of the endocrine system associated with the thyroid gland has been on the rise year by year. Hypothyroidism (hypothyroidim, abbreviated as "Hypothyroidism") belongs to a common endocrine system disease in clinic, and is mainly characterized by decreased synthesis and secretion of thyroid hormone or a syndrome of decreased metabolic level of an organism caused by insufficient physiological effect of thyroid hormone, decreased sympathetic nerve excitation and metabolic rate, accumulation of mucopolysaccharide and the like in skin and tissues as pathological features, and even mucoid edema of severe patients. The clinical treatment of hypothyroidism mainly comprises hormone replacement therapy, wherein the thyroid tablets taking animal thyroid extracts as main active ingredients achieve very excellent curative effects on the clinical treatment of hypothyroidism.
According to the Chinese pharmacopoeia (2015 edition, 198-3) And levothyroxine (levothyroxine, T)4) Two thyroid hormones. The thyroid sheet can protect the damaged thyroid body and has a certain antigen repairing function; meanwhile, the thyroid tablets can directly supplement thyroxine lacking in human bodies, and are very suitable for clinical application of severe hypothyroidism patients with low deiodinase activity.
According to the research, the clinical curative effect of the thyroid tablets is consistent and definite, and meanwhile, the clinical curative effect is extremely related to the biological potency of the thyroid tablets, and the lack of stability of the biological potency is a main factor causing large difference of the clinical curative effect. In order to ensure the stability and clinical effectiveness of thyroid tablets, the main drug effect component T is definitely specified in the 2015 edition Chinese pharmacopoeia3、T4As a quality control index, the standard limit of the main component of the thyroid tablet is specified, and T is required to be performed3、T4The content uniformity is checked, and compared with the original method which takes the content of iodine as a quality control index, the standard is stricter.
According to the chinese pharmacopoeia (2015 edition, 199 pages): the thyroid tablet contains levothyroxine (C) 1mg per day calculated according to the labeled amount of thyroid powder15H11I4NO4，T4) And liothyronine (C)15H12I3NO4，T3) 0.52-0.64 μ g and 0.13-0.15 μ g, respectively. Based on the specification of 40mg, the thyroid tablets with the theoretical tablet weight of 90mg should contain levothyroxine (T)4) 20.8-25.6 mug of liothyronine (T)3) 5.2-6.0 mug of the main drug effect component T4、T3The weight ratio of the tablet is 0.028% and 0.007%. In 2015 edition of Chinese pharmacopoeiaThe investigation of content uniformity is increased, and T in each thyroid tablet is specified4And T3The content uniformity of the component (A) is equal to or less than 20 of A + 2.2S. This standard is very stringent and challenging for a biochemical drug of animal origin and for a product with very low drug content. As for the current state of the current domestic production process and preparation quality, products of most manufacturers do not meet the regulations and are in a production stop state. Therefore, the improvement of the preparation process and the improvement of the product quality are not slow.
The preparation method of the tablet can be roughly divided into two main types of granulation and tabletting methods and whole powder direct tabletting methods. Compared with the granulation and tabletting method, the direct tabletting process of the whole powder is simple, and the drug is prevented from being exposed in the humid, hot and light environments for a long time in the preparation process, so that the degradation of the drug is reduced, and the curative effect is reduced. The direct powder compression method has high requirements on the compressibility and flowability of raw and auxiliary materials, and the flowability and compressibility of most of medicine powder cannot meet the process requirements of direct powder compression.
The thyroid gland material is obtained by dehydrating thyroid gland of edible animal, defatting, drying, etc. The fine structure of the thyroid gland material is a distinct floccule, intertwined in a fibrous form, difficult to crush, and poor in fluidity. The thyroid gland raw material and the auxiliary material have large grain diameter difference and are not uniformly mixed, so that the thyroid gland tablets T are caused3、T4The content is not uniform. Generally, the thyroid gland raw material is difficult to be crushed to reach the granularity required by the direct compression of the powder by the crushing treatment, and the mixed powder mixed with the auxiliary material has poor flowability. Therefore, wet granulation is generally adopted in the process for preparing thyroid tablets by most domestic manufacturers, the preparation process is complex, and the drugs are influenced by factors such as humidity, heat and the like for a long time in the preparation process, so that the drugs are degraded and inactivated, and the potency of the drugs is unstable. The direct powder tabletting process has fewer steps and simple operation; the direct contact of materials with moisture and heat is avoided, and the degradation and inactivation of the medicine are avoided; the product has high quality and stable property, but has higher requirements on the powder property and quality of the raw materials and auxiliary materials and the performance of equipment.
Therefore, the powder property of the thyroid raw material is changed, the mixing uniformity of the raw materials and the auxiliary materials is improved, the prescription process of the thyroid tablet is further optimized, the thyroid tablet is produced by adopting the direct powder tabletting process, the content uniformity of the thyroid tablet is improved, meanwhile, the degradation and inactivation of the thyroid raw material in the production process are avoided, and the stability of the biological value of the thyroid tablet is improved, so that the thyroid tablet has great research and development values.
The invention content is as follows:
the invention aims to provide thyroid tablets produced by directly tabletting whole powder and a preparation process thereof, and particularly provides a synergistic application of calcium hydrogen phosphate for assisting in optimizing the property of thyroid raw material powder and freeze drying for assisting in crushing, so as to prepare thyroid powder capable of directly carrying out powder direct compression, and overcome the defects in the prior art.
In order to achieve the purpose, the invention adopts the following technical scheme:
the thyroid tablets produced by directly tabletting whole powder and the preparation process thereof are characterized in that the formula comprises the following components in percentage by weight:
Figure BSA0000150581080000021
the thyroid powder is composed of a thyroid mixed crushed product and a diluent.
The thyroid gland mixed crushed material is prepared by adopting a synergistic application of calcium hydrophosphate for assisting in optimizing the property function of thyroid gland powder and a freeze-drying auxiliary crushing technology, and is specifically prepared by mixing a thyroid gland raw material and calcium hydrophosphate according to a certain proportion, wetting, freeze-drying and crushing; the calcium hydrophosphate is one or more of anhydrous calcium hydrophosphate and dihydrate calcium hydrophosphate; the mixing ratio of the thyroid gland raw material and calcium hydrophosphate is selected from 1: 0.5-1: 3.5, and the preferred ratio is 1: 2 and 1: 2.5.
The thyroid gland raw material contains floccules, and the raw material is easy to gather again after being purely mechanically crushed; and the bulk density is small, the medicine is fluffy, the toughness is high, the medicine is not easy to be crushed, and the powder property requirement of direct powder tabletting can be hardly met.
According to the specific material properties of the thyroid gland raw material, the following two technologies are selected to optimize the powder properties of the thyroid gland raw material.
The granular substance assists in optimizing the powder property of the thyroid gland raw material: adding a certain amount of granular substances into the thyroid gland raw material to block fibrous adhesion of the raw material, so as to achieve the purpose of assisting the crushing of the thyroid gland raw material and prepare the thyroid gland powder meeting the requirement of direct powder tabletting.
And (3) auxiliary crushing by a freeze drying technology: through material self or additional moisture content, the inside skeleton texture that forms at the in-process of prefreezing of material, the drying back, skeleton texture remains unchanged basically, forms homogeneous porous structure, increases the fragility of material for the material is changeed smashes, the crushing of supplementary thyroid gland raw materials.
The feasibility and the law of action of the two technologies described above were studied according to the following specific embodiments.
The specific scheme is as follows: different granular substances are added into the thyroid gland raw material, the specific granular substances are lactose, calcium hydrophosphate, sucrose, mannitol and microcrystalline cellulose, and multiple experiments show that different granular substances have different influences on the crushing effect of the auxiliary thyroid gland raw material, the sieving rates of 60 meshes, 100 meshes and 200 meshes are used as main evaluation indexes, and the larger the sieving rate is, the better the crushing effect is. The results show that the secondary crushing action of calcium hydrogen phosphate is more excellent.
Calcium hydrogen phosphate has rough surface, high density and no hygroscopicity, and is a common filler for preparation. Further investigating the effect of calcium hydrophosphate for auxiliary crushing, wherein calcium hydrophosphate and a thyroid gland raw material are separately mixed uniformly and then mechanically crushed, the calcium hydrophosphate can be fully dispersed in the middle of thyroid gland raw material tissue fibers in advance, and in the mechanical crushing process, the calcium hydrophosphate with a rough surface and the thyroid gland raw material are rubbed with each other to block fibrous adhesion between the thyroid gland raw materials; meanwhile, the thyroid raw material can be attached to the rough surface of calcium hydrophosphate, so that the integral bulk density is increased, and a better crushing effect is obtained. However, the improvement of the thyroid gland raw material powder property by the method still does not meet the powder property requirement of direct tabletting of the whole powder, and the problems of poor fluidity, slight aggregation of the raw material, too small density, poor mixing uniformity of other auxiliary materials and the like exist.
As the effect of assisting the crushing of the thyroid gland raw material through the freeze drying is considered, a skeleton structure is formed in the thyroid gland raw material in the pre-freezing process, and after the drying is finished, the skeleton structure in the mixed material basically keeps unchanged to form a uniform porous structure, so that the brittleness of the material is improved, the crushing is easier, and the particle size is small. However, the thyroid gland raw material treated by the method does not fundamentally change the fibrous character of the tissue, and when the thyroid gland raw material is placed for a period of time or slight moisture absorption occurs, the fibrous material can reappear, and the material is gathered again. Meanwhile, the flowability of the raw materials treated by the method is not improved to meet the requirement of the powder property for direct tabletting of the powder.
In the specific embodiment, the advantages and the disadvantages of the two methods are found to have the tendency of mutual compensation and synergy, so that the feasibility of further optimizing the crushing effect of the thyroid gland raw material is realized by using the two technologies in a synergistic way. The specific implementation scheme is as follows: calcium hydrogen phosphate and thyroid gland are mixed uniformly in advance, and the mixture is freeze-dried and then crushed. The result shows that the two technologies are used in a synergistic manner, so that the advantages of the two technologies when used independently can be exerted, the defects of the two technologies can be mutually compensated, the powder property of the thyroid gland raw material is improved, and the thyroid gland mixed crushed material which has good fluidity, is not easy to gather and layer, is not easy to absorb moisture and is easy to be uniformly mixed with other auxiliary materials is obtained, so that the thyroid gland powder which can be prepared by directly tabletting the whole powder is obtained.
The preparation method of the thyroid gland mixed crushed material comprises the following specific steps:
(1) preparing a thyroid gland raw material: removing connective tissues and fat tissues on the thyroid gland, and then dehydrating, degreasing, drying and primarily crushing the gland to obtain a thyroid gland raw material;
(2) preparing a mixed material: mixing thyroid gland raw material and calcium hydrogen phosphate uniformly according to a certain proportion;
(3) wetting of the mixed materials: wetting the mixed material by using a solvent; the solvent comprises purified water and a mixed solvent; the mixed solvent consists of ethanol, acetone and water, wherein the proportion range of the water is 0-99%; the solvent can be added with one or more of wetting agents such as poloxamer, tween and sodium dodecyl sulfate, and the proportion range of the wetting agents is 0-15%.
(4) Freezing-drying: loading the wetted mixed material into a freeze-drying tray, wherein the tray loading thickness is not more than 2cm, and freeze-drying in a freeze dryer, and the method specifically comprises the following steps:
a. a pre-freezing stage: rapidly cooling to 5-10 ℃ below the eutectic point of the materials in a freeze dryer, pre-freezing to-40 ℃ below, and keeping the temperature for 2-6 hours; or placing the mixed materials in a refrigerator at the temperature of minus 20 ℃ for pre-freezing until the mixed materials are completely fixed and formed, and placing the mixed materials in a freeze dryer to keep the pre-freezing temperature below minus 40 ℃ for 2-4 hours;
b. a primary sublimation stage: starting a vacuum pump, controlling the temperature between minus 40 ℃ and minus 5 ℃ to sublimate the ice in the material until the sample has no water mark, and ending the stage.
c. A secondary sublimation stage: raising the temperature, raising the temperature of the mixed materials to 10-30 ℃, and continuing for 4-8 hours;
d. and (3) a heat preservation stage: controlling the temperature of the mixed material below 40 ℃, and preserving the heat for 2-6 hours to finish freeze-drying;
(5) crushing: the freeze-dried mixture is pulverized and sieved to obtain a thyroid gland mixed pulverized product with a particle size of 250 μm or less, preferably 150 μm or less, and more preferably 75 μm or less.
The crushing is to reduce the particle size of the freeze-dried mixed material by applying one or more of impact force, compression force, shearing force, bending force and grinding force to the material.
The thyroid gland mixture pulverized product has a particle size of 250 μm or less in an amount of more than 98%, preferably 150 μm or less, and more preferably 75 μm or less.
The diluent is one or a combination of more of sucrose, lactose, sodium chloride and mannitol, and is preferably lactose; the dosage of the diluent is T in the thyroid gland mixed crushed product3、T4Based on the content of (A), adding a diluent to the mixture of T and3、T4diluted content, and each 1mg of thyroid powder contains levothyroxine (C)15H11I4NO4，T4) And liothyronine (C)15H12I3NO4，T3) Should be 0.52 mug to 0.64 mug and 0.13 mug to 0.15 mug, respectively.
The thyroid tablets are characterized in that the filler is selected from one or more of sucrose, dextrin, lactose, microcrystalline cellulose, pregelatinized starch, anhydrous calcium hydrogen phosphate, dihydrate calcium hydrogen phosphate, calcium carbonate, calcium sulfate, dihydrate calcium sulfate, mannitol, sorbitol and sucrose, and preferably from one or more of lactose, microcrystalline cellulose, anhydrous calcium hydrogen phosphate and dihydrate calcium hydrogen phosphate.
The disintegrating agent is selected from one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, microcrystalline cellulose, alginic acid, sodium alginate and carboxymethylcellulose calcium.
The lubricant is selected from one or more of stearic acid, magnesium stearate, talcum powder, hydrogenated vegetable oil, polyethylene glycol, sodium dodecyl sulfate and superfine silica gel powder, and preferably one or more of stearic acid, magnesium stearate and superfine silica gel powder.
The glidant is one or a combination of more of micropowder silica gel, talcum powder and the like, and preferably micropowder silica gel.
The preparation method of the thyroid tablets adopts a direct powder tabletting method to prepare the thyroid tablets, and comprises the following steps:
1) pretreatment of raw materials and auxiliary materials: pulverizing raw materials and adjuvants, and sieving;
2) mixing the components uniformly according to the proportion of the prescription;
3) the tabletting process comprises the following steps: directly tabletting the uniformly mixed powder;
4) coating: coating with gastric soluble coating material, wherein the heating temperature in the whole process cannot exceed 70 ℃.
Compared with the prior art, the invention has the following beneficial effects:
1. the invention creatively applies the calcium hydrophosphate to the optimization of the property of the thyroid gland raw material powder. The calcium hydrophosphate has high density, rough particle surface and almost no hygroscopicity; the thyroid gland raw material has low density and obvious fibrous structure. The crushing in-process of this patent ingenious being applied to thyroid gland raw materials with calcium hydrogen phosphate granule, fully distribute calcium hydrogen phosphate in the fibrous structure of thyroid gland raw materials, in mechanical crushing in-process, the coarse surface of calcium hydrogen phosphate rubs with thyroid gland raw materials each other, effectively cuts off fibrous adhesive linkage in the thyroid gland raw materials, can effectively prevent the reunion of thyroid gland raw materials; simultaneously, the thyroid gland raw materials can be attached to the coarse surface of calcium hydrogen phosphate, help increasing holistic bulk density, be favorable to mixing each other with other auxiliary materials.
2. The invention creatively applies the freeze drying technology to the auxiliary crushing of the thyroid gland raw material. The thyroid gland raw material is subjected to freeze drying, a skeleton structure is formed in the thyroid gland raw material in the pre-freezing process, and after the drying is finished, the skeleton structure in the material is basically kept unchanged to form a uniform porous structure, so that the brittleness of the material is improved, and the material is easier to crush.
3. Based on the principle of 'exerting advantages synergistically and making up defects mutually', the technology for optimizing the properties of thyroid raw material powder by calcium hydrophosphate and the technology for crushing the freeze-drying auxiliary thyroid raw material act synergistically. The result shows that the two technologies are used cooperatively, the crushing effect of the thyroid gland raw material can be further optimized, the powder property of the thyroid gland raw material is improved, the thyroid gland mixed crushed material which has good fluidity, is not easy to gather and layer, is not easy to absorb moisture and is easy to be uniformly mixed with other auxiliary materials is obtained, and therefore the thyroid gland powder which has better fluidity and more uniform content and can be used for preparing full-powder direct tabletting is obtained.
4. Provides the thyroid tablets directly pressed by full powder and the preparation process thereof for the first time. Because of the limitation of the property of the thyroid raw material powder, at present, wet granulation is mainly adopted to prepare thyroid tablets in China. Compared with wet granulation, direct powder compression has certain advantages such as less procedures, simple process, time saving and low costCan accelerate the dissolution of the medicine. The powder property of the thyroid raw material is optimized by cooperating with calcium hydrogen phosphate and a freeze drying technology, and the fluidity and the compressibility of the obtained thyroid mixed crushed material both meet the requirement of direct powder tabletting. The thyroid tablet is prepared by adopting a powder direct compression technology, and the preparation process of the thyroid tablet does not directly contact with dampness and heat, so that the thyroid tablet is more beneficial to the effective component T of the medicine3、T4The stability of (2).
5. Improve the content uniformity of the thyroid powder and the thyroid tablets. The thyroid gland mixed crushed substance is prepared by adopting a method of freeze drying and auxiliary crushing of calcium hydrogen phosphate and thyroid gland raw materials, so that the particle size difference of the raw and auxiliary materials is greatly reduced, and the mixing uniformity of the raw and auxiliary materials is improved. The thyroid tablet is prepared by direct powder tabletting method, and each tablet is calculated according to the labeled amount of thyroid powder, wherein T is measured in each 1mg3： 0.13～0.15μg，T4: 0.52-0.64 mu g of T in thyroid powder3、T4RSD content is less than or equal to 4%, and T in thyroid tablet3And T4The content uniformity accords with the regulation that A +2.2S is less than or equal to 20, the content uniformity of the thyroid tablets is effectively ensured, the biological value of the thyroid tablets is more stable, and the safety and the clinical effectiveness of the thyroid tablets are ensured.
6. The tablets disintegrate more uniformly. The tablets are disintegrated within 15min by checking disintegration time, the disintegration time difference among the tablets is small, and RSD is less than or equal to 5%, so that the stability of product quality and the safety of clinical use are ensured.
Description of the drawings:
FIG. 1 is an appearance diagram of the crushed thyroid gland product treated by different processes. A: direct mechanical pulverization, B: freeze drying and pulverizing.
The specific implementation mode is as follows:
the present invention is described in further detail below with reference to specific examples, which are intended to be illustrative only and not to limit the scope of the present invention.
Example 1
The method is used for investigating the effect of different granular substances on the auxiliary crushing of the thyroid gland raw material, and comprises the following specific embodiments: the addition of lactose, calcium hydrogen phosphate dihydrate, sucrose, mannitol and microcrystalline cellulose has auxiliary effect on the grinding of thyroid gland raw materials. The method comprises the following specific steps:
taking 10g of thyroid gland raw material, respectively adding lactose, calcium hydrogen phosphate dihydrate, sucrose, mannitol and microcrystalline cellulose at a ratio of 1: 2, mixing well, mechanically pulverizing for 3min, and comparing with the material directly mechanically pulverized from thyroid gland raw material.
The particle size and whether the materials are re-aggregated are taken as main investigation indexes, and the materials which are crushed by the aid of the granular materials and directly crushed are compared and analyzed. The method for inspecting the particle size of the material comprises the following steps: the proportion (screening rate) of the materials passing through 60-mesh, 100-mesh and 200-mesh sieves is respectively considered; the investigation method of the material reaggregation comprises the following steps: and respectively stirring the materials which pass through the 60-mesh sieve and the 100-mesh sieve again, sieving for the second time, and comparing the secondary sieving rate of each material.
The results of the specific examples are shown in tables 1 and 2, and calcium hydrogen phosphate dihydrate has more outstanding auxiliary pulverization effects than other substances. Although the calcium hydrogen phosphate dihydrate can improve the powder property of the thyroid gland raw material, the improvement of the powder property of the thyroid gland raw material treated by the method still does not meet the powder property requirement of direct tabletting of the whole powder, and the problems of poor fluidity, slight aggregation of the raw material, poor mixing uniformity of the raw material and other auxiliary materials and the like exist.
TABLE 1 influence of different particulate materials on the particle size of thyroid gland-assisted comminution
Figure BSA0000150581080000071
TABLE 2 Effect of different particulate materials on thyroid-assisted comminution on reaggregation
Figure BSA0000150581080000072
Example 2
The auxiliary effect of the freeze drying technology on the auxiliary grinding of the thyroid gland raw material is considered and compared with the direct grinding.
10g of the treated thyroid gland material is mechanically pulverized and sieved for 3 min.
Taking another 10g of the treated thyroid gland raw material, and carrying out freeze drying and auxiliary crushing, wherein the specific steps are as follows:
(1) preparation of lyophilized sample of thyroid material
10g of the treated thyroid gland raw material is taken, 50mL of water is added, stirred and fully infiltrated. The wetted sample was spread on a freeze-drying tray at a thickness of about 1cm and placed in a freeze-dryer for use.
(2) Freeze-drying
The samples were placed in a lyophilizer and lyophilized according to the following lyophilization procedure.
a. A pre-freezing stage: starting a freeze dryer, setting the pre-freezing temperature to be-40 ℃, and keeping the temperature for 2-6 hours until all thyroid gland raw materials are fixed and formed;
b. a primary sublimation stage: starting a vacuum pump, setting the temperature to be-30 ℃, sublimating ice in the materials until the sample has no water mark, and ending the stage;
c. a secondary sublimation stage: raising the temperature, raising the temperature of the thyroid gland raw material to 20 ℃, and continuing for 4-8 hours;
d. and (3) a heat preservation stage: controlling the temperature of the thyroid gland raw material below 35 ℃, and preserving the heat for 2-6 h to finish freeze-drying.
(3) Pulverizing
And (3) crushing and sieving the freeze-dried thyroid gland raw material by a shear type crusher.
The results of the specific examples are shown in table 3, and the freeze-drying-assisted pulverization process can improve the pulverization effect of the thyroid gland raw material, by examining the particle size of the ground thyroid gland product. After freeze drying, the brittleness of the thyroid gland raw material is increased, the thyroid gland raw material is easier to crush, and the obtained particles have smaller and more uniform particle size. As shown in the attached figure 1 of the specification, compared with direct mechanical crushing, the freeze drying auxiliary crushing technology can solve the problems of fluffy substances and obvious floccules, so that the materials are easy to crush, and the particle size of the materials is effectively reduced. However, the flowability of the raw material treated by the method is poor, and the flowability of mixed powder prepared from the corresponding raw material is poor, so that the requirement of direct powder compression cannot be met.
TABLE 3 comparison of powder Properties of thyroid gland pulverized material prepared by different processes
Figure BSA0000150581080000081
Moreover, the thyroid gland raw material treated by the method does not fundamentally change the fibrous character of the tissue, and when the thyroid gland raw material is placed for a period of time or slight moisture absorption occurs, the fibrous material can reappear, and the material is gathered again. The sieved material was sieved twice as shown in table 4, and the results show that: the thyroid gland raw material crushed by freeze drying assistance has the phenomenon of reaggregation, and is not beneficial to being uniformly mixed with auxiliary materials, so that the method needs to be further improved, and the reaggregation of the crushed raw material is avoided.
TABLE 4 Effect of freeze-drying assisted thyroid comminution on reaggregation
Figure BSA0000150581080000082
Example 3
According to the embodiment 1 and the embodiment 2, the calcium hydrophosphate auxiliary crushing technology and the freeze drying technology have respective advantages and disadvantages, and the advantages and disadvantages of the two technologies used independently have the tendency of mutual compensation and synergy, so that the two technologies are synergistically used to further optimize the crushing effect of the thyroid gland raw material.
The specific implementation scheme is as follows: after 20g of calcium hydrogen phosphate and 10g of thyroid gland raw material were mixed uniformly, calcium hydrogen phosphate particles were uniformly and sufficiently filled in the thyroid gland raw material, and after wetting with 50mL of purified water, the operation was performed according to the freeze-drying procedure of table 5.
TABLE 5 Freeze drying protocol
Figure BSA0000150581080000083
The mixture was lyophilized and then pulverized. The results are shown in Table 6: the two technologies are used in a synergistic manner, so that the advantages of the two technologies when used independently can be exerted, the defects of the two technologies can be more mutually compensated, the powder property of the thyroid gland raw material is improved, and the thyroid gland mixed crushed material which is not easy to gather and layer, not easy to absorb moisture, good in flowability and easy to be uniformly mixed with other auxiliary materials is obtained, so that the thyroid gland powder which can be prepared by directly tabletting the whole powder is obtained.
TABLE 6 Effect of synergistic calcium Hydrogen phosphate and Freeze-drying assisted comminution technique
Figure BSA0000150581080000091
Example 4
And (3) investigating whether the synergistic use of other granular substances and a freeze-drying technology can improve the auxiliary crushing effect.
The specific implementation steps are as follows:
(1) wetting of the mixed materials: weighing 10g of thyroid gland raw material, adding lactose, calcium hydrophosphate, microcrystalline cellulose, sucrose and mannitol according to the proportion of 1: 1 and 1: 2 respectively, uniformly mixing, adding 50mL of purified water, and immediately stirring to fully infiltrate the mixture.
(2) Freezing-drying: the wetted mixture was placed in a freeze-drying tray having a thickness of about 1cm and freeze-dried in a freeze-dryer, the freeze-drying procedure being as described in table 5 of example 3.
(3) Crushing: and crushing and sieving the freeze-dried mixed material.
Through investigation and comparison of the influence of different granular substances on the crushing of the thyroid raw material under the synergistic effect of the freeze-drying technology, the appearance after freeze-drying and the sieving rate of 200 meshes are used as main evaluation indexes, and the results show that the appearance after freeze-drying of the thyroid raw material can be smooth and full due to the addition of lactose, calcium hydrogen phosphate and sucrose, the sieving rate is further improved, and the crushed materials are not easy to gather again, which shows that the freeze-drying technology can obviously improve the crushing effect of the thyroid raw material, and meanwhile, the granular substances with different characteristics are added, so that the advantages of the granular substances can be applied to the crushing of the thyroid raw material, and the powder property of the thyroid raw material is optimized. The results are shown in Table 7, where the thyroid material is used synergistically with calcium hydrogen phosphate, the effect is the best. Therefore, the thyroid gland raw material and the calcium hydrophosphate are more complementary in powder property and are used cooperatively, and the effect is optimal.
TABLE 7 Effect of different particulate materials on the assisted comminution of thyroid gland material
Figure BSA0000150581080000092
Compared with other substances, the calcium hydrophosphate has a rough surface structure, can contact with a thyroid raw material by utilizing the rough surface, breaks the original tissue adhesion structure of the thyroid raw material through mutual friction with the thyroid raw material, is beneficial to improving the crushing effect of the thyroid raw material, and can prevent the thyroid raw material from reaggregating; secondly, calcium hydrogen phosphate has great density, and mixing it with the thyroid gland raw materials is favorable to increasing the density of whole material, makes the raw and auxiliary materials mix more evenly.
When the grinding device and the freeze-drying technology act cooperatively, after the thyroid gland raw material calcium hydrophosphate mixture is subjected to freeze-drying treatment, the thyroid gland raw material calcium hydrophosphate mixture and the thyroid gland raw material are contacted more tightly, the friction efficiency between the calcium hydrophosphate and the thyroid gland raw material is enhanced in the grinding process, and the effect of calcium hydrophosphate on auxiliary grinding is enhanced. Meanwhile, the freeze drying technology can effectively improve the phenomenon that the thyroid gland raw material is too fluffy, and can make up the defect of auxiliary crushing by independently using calcium hydrophosphate.
Example 5
Investigating the influence of different freeze-drying conditions on crushing of the mixed materials, respectively preparing 1705-1, 1705-2 and 1705-3 batches of thyroid gland mixed crushed materials according to the following steps, and evaluating and comparing the thyroid gland mixed crushed materials, wherein the specific steps are as follows:
taking 25g of the treated thyroid gland raw material, adding 70g of anhydrous calcium hydrogen phosphate, uniformly mixing, adding 125mL of water, and immediately stirring to fully soak the thyroid gland raw material. The wetted sample was spread on a freeze-drying tray, about 1cm thick, and placed in a freeze-dryer for processing. The specific lyophilization protocol is described in tables 8, 9, and 10. After the freeze-drying is finished, the freeze-dried product is mechanically crushed and sieved.
TABLE 81705-1 Freeze drying procedure
Figure BSA0000150581080000101
TABLE 91705-2 Freeze drying procedure
Figure BSA0000150581080000102
TABLE 101705-3 Freeze-drying protocol
Figure BSA0000150581080000103
The moisture content, the screening rate and the appearance of the freeze-dried material are used as main evaluation indexes to evaluate and compare the thyroid gland mixed crushed material. As shown in table 11, the freeze-drying conditions were varied within a certain range, and the sieving rate, appearance and drug content were not significantly changed. The moisture content of the material can be slightly changed due to the change of the freeze-drying parameters, and experiments prove that the change of the moisture content to the certain degree can not obviously influence the preparation and tabletting of mixed powder.
TABLE 11 Effect of varying Freeze drying parameters on the Effect of supplemental comminution
Figure BSA0000150581080000111
Example 6
Under the condition of constant freeze-drying parameters, the auxiliary effect of the type and concentration of the wetting agent on the crushing of the mixed material is examined. The procedure is as follows, and the results are shown in Table 13.
The method comprises the following specific steps:
(1) wetting of the mixed materials: weighing 5g of thyroid gland raw material, adding 15g of calcium hydrogen phosphate dihydrate, mixing uniformly, adding 25mL of wetting agents with different types or concentrations (the specific embodiment of the wetting agent is shown in Table 13), and stirring immediately to fully soak the thyroid gland raw material.
(2) Freezing-drying: the wetted mixture was placed in a freeze-drying tray having a thickness of about 1cm and freeze-dried in a freeze-dryer, the freeze-drying procedure being as described in Table 12.
Table 12 lyophilization schedule for example 6
Figure BSA0000150581080000112
(3) Crushing: and crushing and sieving the freeze-dried mixed material.
By investigating the influence of the type and concentration of the added wetting agent on the auxiliary crushing of the freeze-drying of the mixed material, and taking the appearance after freeze-drying and the sieving rate of 200 meshes as main evaluation indexes, the result shows that the addition of the wetting agent can improve the appearance of the mixed material after freeze-drying, but has no significant influence on the sieving rate.
TABLE 13 influence of wetting agent type and concentration on lyophilization-assisted comminution
Figure BSA0000150581080000113
Example 7
The thyroid powder is prepared by uniformly mixing a thyroid mixed crushed product and a diluent. According to T in the thyroid gland mixed crushed material3、 T4Adding appropriate amount of diluent to make 1mg of liothyronine (C) in thyroid powder15H12I3NO4，T3) And levothyroxine (C)15H11I4NO4，T4) 0.13 to 0.15 mug and 0.52 to 0.64 mug respectively, which meet the pharmacopoeia regulations. In thyroid powder T3、T4Within the specified range, the higher the content uniformity, the more favorable the product has stable curative effect.
Using sucrose, lactose, sodium chloride and starch as diluents, and uniformly mixing with the freeze-dried mixture to obtain a mixture T3、T4In the specificationWithin the specified range. Comparing T in thyroid powder prepared from the four diluents3、T4The results are shown in Table 14. After the thyroid powder is prepared from the mixture of calcium hydrogen phosphate auxiliary grinding and freeze-drying auxiliary grinding co-processing3、 T4The relative standard deviation of the content of the powder is less than 4 percent and is far superior to the thyroid powder prepared by direct crushing process treatment. In order to obtain a raw material with better fluidity, the diluent selects an auxiliary material which is suitable for directly tabletting powder and has good fluidity.
TABLE 14 thyroid powders with different diluents T3、T4Content uniformity of
Figure BSA0000150581080000121
Example 8
The main factors of the whole powder direct compression method different from the wet granulation compression method are as follows: the material for directly tabletting the whole powder is powdery fine powder, and the quality of the product is directly determined by the fluidity and the compressibility of the material. The preparation and the quality of the tablets are directly influenced by the quality of the fluidity of the mixed powder for tabletting, and the possibility that the thyroid gland raw material can be directly tableted by adding auxiliary materials to assist in improving the fluidity of the mixed powder by changing the powder property of the thyroid gland raw material is realized.
The fluidity and compressibility of the material were evaluated using the angle of repose and the Carl index as indices, and the specific requirements are shown in Table 15. Comparing the flowability of the thyroid powder prepared by freeze-drying assisted pulverization and direct mechanical pulverization of calcium hydrogen phosphate and the thyroid raw material, the result is shown in table 16, and the thyroid powder prepared from the directly pulverized thyroid raw material has extremely poor powder flowability and compressibility; the freeze-drying auxiliary crushing of the calcium hydrogen phosphate and the thyroid gland raw materials is beneficial to improving the powder flowability and compressibility of the thyroid gland powder, so that the thyroid gland powder can be produced by directly tabletting the powder. Adding the auxiliary materials according to the prescription amount, investigating the fluidity of the mixed powder before tabletting, and further determining the superiority of the freeze-drying auxiliary crushing technology of the calcium hydrophosphate and the thyroid gland raw material.
TABLE 15 evaluation indexes of powder flowability and compressibility
Figure BSA0000150581080000122
TABLE 16 Effect of the comminution Process on the flowability of the thyroid powder
Figure BSA0000150581080000123
The powders for tableting were mixed in the prescribed proportions as claimed in the claims and their flowability was further investigated. As shown in table 17, the thyroid powders were mixed with other excipients, and then the fluidity of the mixed powders was superior to that of the thyroid powders with the aid of the excipients having good fluidity and compressibility. Comparing the fluidity of the mixed powder prepared by using the thyroid powder prepared by freeze-drying assisted crushing and direct mechanical crushing of the calcium hydrogen phosphate and the thyroid gland raw material as the raw material, the fluidity of the mixed powder is obviously improved after the thyroid powder prepared by using the freeze-drying assisted crushing process of the calcium hydrogen phosphate and the thyroid gland raw material is added with the auxiliary materials in the prescription amount, and the mixed powder-1, the mixed powder-2 and the mixed powder-3 shown in table 17 can be directly tableted. The thyroid powder prepared by the direct mechanical pulverization process still has poor fluidity after the auxiliary materials with the prescription amount are added, and the thyroid powder cannot be directly tabletted as the mixed powder-4 shown in the table 17.
TABLE 17 investigation of the flowability of thyroid tablets
Figure BSA0000150581080000131
Example 9
Thyroid tablets are prepared by the powder direct compression method, which is described in detail by the preferred three-size formulation.
The first prescription is as follows: the specification is 65 mg/tablet, the tablet weight is about 150mg, and the specific prescription composition is shown in Table 18.
TABLE 18 prescription composition of prescription one (65 mg/tablet)
Figure BSA0000150581080000132
The specific process steps of the first prescription are as follows:
1) pretreatment of raw materials and auxiliary materials: weighing 65g of thyroid powder, and sieving the thyroid powder by a 200-mesh sieve for later use; weighing the diluent and the disintegrant according to the corresponding proportion, respectively sieving with a 100-mesh sieve for later use, and mixing the thyroid powder and the auxiliary materials for 20 minutes; adding the prescription dose of superfine silica gel powder, stearic acid and magnesium stearate, and mixing for 10 minutes.
2) The tabletting process comprises the following steps: cleaning a matched punch and a matched die ring, and correctly installing and detecting the punch and the die ring for later use; adding the powder into a hopper, tabletting according to theoretical tablet weight, checking the tabletting quality by taking the appearance, hardness and average tablet weight of a tablet core as main evaluation indexes, and controlling the tablet weight: 138.75 mg-161.25 mg, the difference limit of tablet weight is + -7.5%;
3) coating: accurately weighing the coating solution according to the prescription amount, slowly adding the coating solution into a stirring pot while stirring, and stirring for 40-120 min for later use; and pouring the qualified tablet cores into a high-efficiency coating pot, spraying the coating liquid, controlling the air inlet temperature below 70 ℃ in the spraying process, spraying for 4-5 hours, and blowing to room temperature by cold air after spraying.
And a second prescription: the specification is 40 mg/tablet, the tablet weight is about 90mg, and the specific prescription composition is shown in Table 19.
Prescription composition of prescription two (40 mg/tablet) in Table 19
Figure BSA0000150581080000141
The specific process steps of the second formula are as follows:
1) pretreatment of raw materials and auxiliary materials: weighing 40g of thyroid powder, and sieving the thyroid powder by a 200-mesh sieve for later use; weighing the diluent and the disintegrant according to the corresponding proportion, respectively sieving with a 100-mesh sieve for later use, and mixing the thyroid powder and the auxiliary materials for 20 min; adding the prescription dose of superfine silica gel powder, stearic acid and magnesium stearate, and mixing for 10 minutes.
2) The tabletting process comprises the following steps: cleaning a matched punch and a matched die ring, and correctly installing and detecting the punch and the die ring for later use; adding the powder into a hopper, tabletting according to theoretical tablet weight, checking the tabletting quality by taking the appearance, hardness and average tablet weight of a tablet core as main evaluation indexes, and controlling the tablet weight: 83.28mg to 96.75mg, and the difference limit of tablet weight is +/-7.5 percent;
3) coating: accurately weighing the coating solution according to the prescription amount, slowly adding the coating solution into a stirring pot while stirring, and stirring for 40-120 min for later use; and pouring the qualified tablet cores into a high-efficiency coating pot, spraying the coating liquid, controlling the air inlet temperature below 70 ℃ in the spraying process, spraying for 4-5 hours, and blowing to room temperature by cold air after spraying.
And a third prescription: the specification is 32.5 mg/tablet, the tablet weight is about 75mg, and the specific prescription composition is shown in Table 20.
TABLE 20 prescription composition of prescription III (32.5 mg/tablet)
Figure BSA0000150581080000142
The third prescription comprises the following specific process steps:
1) pretreatment of raw materials and auxiliary materials: weighing 32.5g of thyroid powder, and sieving with a 200-mesh sieve for later use; weighing the diluent and the disintegrant according to the corresponding proportion, respectively sieving with a 100-mesh sieve for later use, and mixing the thyroid powder and the auxiliary materials for 20 min; adding the prescription dose of superfine silica gel powder, stearic acid and magnesium stearate, and mixing for 10 minutes.
2) The tabletting process comprises the following steps: cleaning a matched punch and a matched die ring, and correctly installing and detecting the punch and the die ring for later use; adding the powder into a hopper, tabletting according to theoretical tablet weight, checking the tabletting quality by taking the appearance, hardness and average tablet weight of a tablet core as main evaluation indexes, and controlling the tablet weight: 69.38 mg-80.63 mg, wherein the difference limit of tablet weight is +/-7.5%;
3) coating: accurately weighing the coating solution according to the prescription amount, slowly adding the coating solution into a stirring pot while stirring, and stirring for 40-120 min for later use; and pouring the qualified tablet cores into a high-efficiency coating pot, spraying the coating liquid, controlling the air inlet temperature below 70 ℃ in the spraying process, spraying for 4-5 hours, and blowing to room temperature by cold air after spraying.
Example 10
Thyroid tablets (lot Nos. 170509, 170510, 170511) were preliminarily evaluated using the appearance of the tablets, friability, and disintegration time as main evaluation indices. Determination of disintegration time limit: taking 6 test pieces, respectively placing in glass tubes of hanging baskets, placing in a beaker filled with artificial gastric juice at 37 +/-1 ℃, starting a disintegration tester for inspection, and completely disintegrating each piece within 30min to meet the standard. As a result, as shown in Table 21, the appearance of the tablet appeared pale yellow; the friability is less than 1 percent, and meets the requirement; the thyroid tablets are completely disintegrated within 15min, the time for complete disintegration is uniform, and the RSD is less than 5%.
TABLE 21 quality evaluation of thyroid tablets
Figure BSA0000150581080000151
Example 11
Thyroid tablets (batch numbers: 170509, 170510, 170511) prepared by adopting the preferred prescription and process of the invention are according to 2015 version Chinese pharmacopoeia standard for T3、T4The content of (b) was measured, and the content uniformity thereof was examined, and the results are shown in Table 22. A +2.2S is less than 20, and conforms to the pharmacopoeia regulations.
TABLE 22 thyroid tablets T3、T4Content and content uniformity
Figure BSA0000150581080000152
The above-mentioned embodiments are intended to illustrate the objects, technical solutions and advantages of the present invention, and it should be understood that the above-mentioned embodiments are only exemplary embodiments of the present invention, and are not intended to limit the present invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (8)

1. The thyroid tablets produced by directly tabletting whole powder are characterized in that the formula comprises the following components in percentage by weight:
Figure FSB0000192472040000011
the sum of the weight percentages of all the components is 100 percent;
wherein the thyroid powder is prepared from thyroid mixed crushed material and diluent;
the thyroid gland mixed crushed material is obtained by adopting a thyroid gland powder property effect optimized by cooperating with calcium hydrophosphate and a freeze-drying auxiliary crushing technology, and is specifically obtained by mixing a thyroid gland raw material and calcium hydrophosphate according to a certain proportion, wetting, freeze-drying and crushing;
the mixing ratio of the thyroid gland raw material and calcium hydrophosphate is selected to be 1: 0.5-1: 3.5;
the calcium hydrophosphate is one or more of anhydrous calcium hydrophosphate and dihydrate calcium hydrophosphate;
the preparation method of the thyroid gland mixed crushed material comprises the following specific steps:
(1) preparing a thyroid gland raw material: removing connective tissues and fat tissues on the thyroid gland, and then dehydrating, degreasing, drying and primarily crushing the gland to obtain a thyroid gland raw material;
(2) preparing a mixed material: mixing thyroid gland raw material and calcium hydrogen phosphate proportionally;
(3) wetting of the mixed materials: wetting the mixed material by using a solvent; the solvent comprises purified water and a mixed solvent; the mixed solvent consists of ethanol, acetone and water, wherein the proportion of the water is below 99 percent; the solvent contains wetting agent, including poloxamer, tween and/or sodium dodecyl sulfate; the proportion range of the wetting agent is below 15%;
(4) freezing-drying: loading the wetted mixed material into a freeze-drying tray, wherein the tray loading thickness is not more than 2cm, and freeze-drying in a freeze dryer, and the method specifically comprises the following steps:
a. a pre-freezing stage: rapidly cooling to 5-10 ℃ below the eutectic point of the materials in a freeze dryer, pre-freezing to-40 ℃ below, and keeping the temperature for 2-6 hours; or placing the mixed materials in a refrigerator at the temperature of minus 20 ℃ for pre-freezing until the mixed materials are completely fixed and formed, and placing the mixed materials in a freeze dryer to keep the pre-freezing temperature below minus 40 ℃ for 2-4 hours;
b. a primary sublimation stage: starting a vacuum pump, controlling the temperature between minus 40 ℃ and minus 5 ℃ to sublimate ice in the material until no water mark exists in the sample, and ending the stage; keeping the temperature at-40 ℃ to-5 ℃ until the sample has no water mark, and ending the stage;
c. a secondary sublimation stage: raising the temperature, raising the temperature of the mixed materials to 10-30 ℃, and continuing for 4-8 hours;
d. and (3) a heat preservation stage: controlling the temperature of the mixed material below 40 ℃, and preserving the heat for 2-6 hours to finish freeze-drying;
(5) crushing: and crushing and sieving the freeze-dried mixed material to obtain the thyroid gland mixed crushed material.
2. The thyroid tablet produced by direct whole powder compression according to claim 1, wherein the diluent in the thyroid powder is one or more of sucrose, lactose, sodium chloride and mannitol; the diluent is used in the amount of liothyronine T in the thyroid gland mixed and crushed material3Levothyroxine T4Based on the content of (A), every 1mg of thyroid powder contains T3、T4The content of the (B) is 0.13-0.15 mug and 0.52-0.64 mug respectively.
3. Thyroid tablets produced by whole powder direct compression according to claim 1, wherein the filler is selected from the group consisting of dextrin, lactose, microcrystalline cellulose, pregelatinized starch, anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, calcium carbonate, calcium sulfate, dibasic calcium sulfate dihydrate, mannitol, sorbitol, sucrose, or a combination thereof.
4. The thyroid tablet produced by full-powder direct compression according to claim 1, wherein the disintegrating agent is selected from one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, microcrystalline cellulose, alginic acid, sodium alginate and carboxymethylcellulose calcium.
5. The thyroid tablets produced by direct whole powder compression according to claim 1, wherein the lubricant is selected from one or more of stearic acid, magnesium stearate, talcum powder, hydrogenated vegetable oil, polyethylene glycol, sodium lauryl sulfate and superfine silica gel powder.
6. The thyroid tablet produced by direct whole powder compression according to claim 1, wherein the glidant is one or more of micropowder silica gel and talcum powder.
7. The thyroid tablet produced by direct whole powder compression according to claim 1, wherein the crushing process of the step (5) of preparing the thyroid gland mixed crushed material is to reduce the particle size of the freeze-dried mixed material by applying one or more of impact force, compression force, shearing force, bending force and grinding force to the material; the particle size of the thyroid gland mixed crushed material is reduced to be within the particle size range of below 250 mu m.
8. The thyroid tablet produced by full powder direct compression according to claim 1, wherein the preparation process is to prepare the thyroid tablet by a powder direct compression method, and comprises the following steps:
(1) pulverizing the raw materials and adjuvants, and sieving;
(2) mixing the components uniformly according to the proportion of the prescription;
(3) directly tabletting the uniformly mixed powder;
(4) coating with gastric-soluble coating material.
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