Medicine tablet as well as preparation method and application thereof

Abstract

The invention discloses a medicine tablet as well as a preparation method and application thereof. The medicine tablet is an amorphous tablet; the medicine tablet comprises an inorganic mineral and an active medicine, wherein the inorganic mineral is a combination of one or more than two inorganic calcium salts, and the structural water content of the inorganic mineral is 1-16%; the active medicine is solid, the content of the active medicine is less than or equal to 10%, and the percentage is the mass percentage of the active medicine in the medicine tablet. The medicine tablet is an amorphous tablet, and the medicine is uniformly distributed in the medicine tablet, so that the activity of the medicine is kept, and the effect of long-acting release of the medicine driven by an inorganic mineral crystallization process is also realized.

Description

TECHNICAL FIELD

[0001] The present application relates to a drug tablet and its preparation method and application. BACKGROUND

[0002] Long-acting controlled release formulations can maintain the slow release of drugs for weeks, months or even years; compared with short-acting release formulations, they can significantly reduce the frequency of administration and improve the compliance of patients. This is particularly important for drugs with short half-lives in vivo, because long-acting formulations can achieve long-term maintenance of drug efficacy through a single administration, which has shown significant advantages in the treatment of diseases such as tumors, autoimmune diseases and bone-related diseases.

[0003] The release mechanisms of long-acting formulations mainly include the following four types: 1) dissolution-driven release mechanism of poorly water-soluble drugs, 2) polymer degradation-driven drug release mechanism, 3) diffusion-driven drug release mechanism of non-degradable implants, and 4) diffusion / swelling / molecular interaction-driven drug release mechanism of hydrogels. However, how to accurately control the long-term release of drugs remains a challenge, which seriously hinders the development of long-acting controlled release drugs.

[0004] In the preparation process of traditional tablets, excipients are usually introduced, which can adhere drugs together under pressure, but also reduce the activity of drugs. In addition, the discontinuity of amorphous biomaterial structure during the tabletting process will directly affect the long-term release performance of drugs and become another obstacle.

[0005] Therefore, the development of new long-acting and precisely controllable release formulation forms has very important practical significance for fully exerting the efficacy of drugs and reducing the need for frequent administration, and is expected to provide new processing means for the development of various drug formulations, which has great market value. SUMMARY

[0006] The technical problem to be solved by the present application is to overcome the defects of the prior art that it is difficult to achieve long-term controlled release of drugs while retaining drug activity, and to provide a drug tablet and its preparation method and application. The drug tablet of the present application is an amorphous tablet, and the drug is uniformly distributed in the drug tablet, which not only maintains the activity of the drug, but also achieves the effect of long-term release of the drug driven by the crystallization process of inorganic minerals.

[0007] The present application solves the above technical problems by the following technical solutions.

[0008] In a first aspect, the present application provides a pharmaceutical tablet, which is an amorphous tablet; the pharmaceutical tablet comprises inorganic minerals and active drugs; wherein the inorganic minerals are a combination of one or more than two inorganic calcium salts, the structural water content of the inorganic minerals is 1-16%; the active drugs are solid, and the content of the active drugs is ≤10%, the percentage being the mass percentage of the active drugs in the pharmaceutical tablet.

[0009] In the present application, preferably, in the pharmaceutical tablet, the interfaces between the particles of the inorganic minerals are interface fusion. The active drugs are uniformly dispersed in the fused inorganic mineral interfaces, which can effectively avoid the aggregation of the active drugs and more accurately regulate the drug release process.

[0010] In the present application, the inorganic calcium salt can be selected from one or more of calcium carbonate, calcium phosphate, calcium oxalate, calcium oxide, calcium chloride, calcium hydrogen phosphate and calcium manganate.

[0011] The present application can more accurately regulate the release kinetics of drugs by utilizing the crystallization kinetics of inorganic minerals and selecting different types and proportions of inorganic minerals.

[0012] In the present application, the inorganic minerals are a combination of one or more than two inorganic calcium salts. It can be understood that the inorganic minerals can be any one of the above seven inorganic calcium salts; it can also be a combination of any two, such as "calcium carbonate and calcium phosphate"; it can also be a combination of any three, such as "calcium phosphate, calcium oxalate and calcium oxide", or "calcium carbonate, calcium phosphate and calcium manganate"; it can also be a combination of any four, such as "calcium carbonate, calcium phosphate, calcium oxide and calcium hydrogen phosphate"; it can also be a combination of any five, such as "calcium carbonate, calcium phosphate, calcium oxide, calcium chloride and calcium hydrogen phosphate"; it can also be a combination of any six, such as "calcium carbonate, calcium phosphate, calcium oxalate, calcium oxide, calcium chloride and calcium manganate"; it can also be a combination of any seven, such as "calcium carbonate, calcium phosphate, calcium oxalate, calcium oxide, calcium chloride, calcium hydrogen phosphate and calcium manganate".

[0013] In the present application, when the inorganic mineral components are combined, the substances can be combined in any ratio. For example, when the inorganic mineral components are a combination of "calcium carbonate and calcium phosphate", the mass ratio of calcium carbonate to calcium phosphate is 1:3, 1:2, 1:1, 2:1 or 3:1. For another example, when the inorganic mineral components are a combination of "calcium phosphate, calcium oxalate and calcium oxide" or a combination of "calcium carbonate, calcium phosphate and calcium manganate", the mass ratio of the combination of inorganic calcium salts is 1:3:2. For another example, when the inorganic mineral components are a combination of "calcium carbonate, calcium phosphate, calcium oxide and calcium hydrogen phosphate", the mass ratio of the combination of inorganic calcium salts is 1:2:3:2. For another example, when the inorganic mineral components are a combination of "calcium carbonate, calcium phosphate, calcium oxide, calcium chloride and calcium hydrogen phosphate", the mass ratio of the combination of inorganic calcium salts is 1:4:7:2:5. For another example, when the inorganic mineral components are a combination of "calcium carbonate, calcium phosphate, calcium oxalate, calcium oxide, calcium chloride and calcium manganate", the mass ratio of the combination of inorganic calcium salts is 1:4:4:3:9:5. For another example, when the inorganic mineral components are a combination of "calcium carbonate, calcium phosphate, calcium oxalate, calcium oxide, calcium chloride, calcium hydrogen phosphate and calcium manganate", the mass ratio of the combination of inorganic calcium salts is 1:3:4:5:6:4:1.

[0014] In the present application, the structural water content of the inorganic mineral is preferably 1%, 2%, 3%, 7%, 11% or 16%. The "structural water" referred to in the present application is also known as "combined water", which is water existing in the form of H + , (OH) - , (H3O) + , etc. in the crystal lattice of a compound or a mineral. By optimizing the structural water content of the inorganic mineral, the fusion of inorganic mineral particles can be effectively achieved, while avoiding the crystallization of drug tablets.

[0015] In the present application, the content of the active drug can be 0.000001-10%, for example, 0.000001%, 0.00001%, 0.0001%, 0.001%, 0.01%, 0.1%, 0.3%, 1%, 3%, 5% or 10%, preferably 1-10%.

[0016] In the present application, the active drug can be selected from one or more of natural drugs, chemically synthesized drugs and biosynthetically synthesized drugs.

[0017] The natural medicine can be selected from Chinese patent medicines and / or natural herbs, and is preferably one or more of flavonoids, alkaloids, lignans, coumarins, saponins and cardiac glycosides, such as one or more of flavone, quercetin, tea polyphenol, anisodamine, dicumarol, acenocoumarol, phenprocoumon, digoxin, deslanoside, digitoxin, astragalus, liquorice, sophora, pueraria, schisandra, psoralea, magnolia and scutellaria.

[0018] The chemical synthetic medicine is a compound obtained through a chemical synthetic route, and is preferably one or more of quinolones, sulfonamides, trimethoprim, nitroimidazoles, nitrofurans, oxazolidinones, steroid hormones, semi-synthetic antibiotics, nervous system drugs, cardiovascular treatment drugs and chemotherapy drugs for malignant tumors, such as one or more of nirmatrelvir, ritonavir, monalizvir, azithromycin and methimazole.

[0019] The biosynthetic medicine is a medicine obtained through genetic recombination, nucleic acid synthesis, cell engineering or fermentation biotechnology, and is preferably one or more of cytokine drugs, nucleic acid drugs and protein drugs, such as one or more of recombinant human interleukin 2, albumin, antibodies, glucose oxidase and insulin.

[0020] The active medicine is suitable for, for example, a combination of flavones and ritonavir, a combination of cytokine drugs, alkaloids and nirmatrelvir, or a combination of lignans, cardiac glycosides, methimazole and nucleic acid drugs.

[0021] In the present application, the medicine tablet can not include excipients commonly used in the art. As described above, excipients can bind medicines, but at the same time, they can also reduce the activity of the medicine. The medicine tablet provided by the present application can maintain a high drug activity without using excipients.

[0022] In a second aspect, the present application provides a preparation method of the above-mentioned medicine tablet, which comprises the following steps: tabletting a mixture of an active medicine and an inorganic mineral to obtain a medicine tablet; the inorganic mineral has a structural water content of 1-16% before tabletting, and the tabletting pressure is 0.1-10 GPa.

[0023] In the present application, the inorganic mineral preferably has a structural water content of 1%, 2%, 3%, 7%, 11% or 16% before tabletting.

[0024] In the present application, the structural water content of the inorganic mineral before tabletting can be achieved by adjusting the process parameters of drying. Preferably, the inorganic mineral is dried before tabletting, the drying temperature is 70℃, and the drying time is 3h-3d. For example, the inorganic mineral is dried at 70℃ for 3h, and the structural water content is 16%; for another example, the inorganic mineral is dried at 70℃ for 6h, and the structural water content is 11%; for another example, the inorganic mineral is dried at 70℃ for 12h, and the structural water content is 7%; for another example, the inorganic mineral is dried at 70℃ for 24h, and the structural water content is 3%; for another example, the inorganic mineral is dried at 70℃ for 2d, and the structural water content is 2%; for another example, the inorganic mineral is dried at 70℃ for 3d, and the structural water content is 1%.

[0025] In the present application, the particle size of the inorganic mineral before tabletting can be 10-1000nm, such as 50nm or 200nm.

[0026] In the present application, the mixture can be placed in a mold for tabletting. The mold can be a metal mold, preferably a stainless steel mold; more preferably, the shape of the stainless steel mold is circular, triangular or polygonal. A mechanical press can be used to apply pressure.

[0027] In the present application, the pressure value of the tabletting can be 0.1GPa, 0.25GPa, 0.5GPa, 0.76GPa, 1GPa, 1.2GPa, 1.5GPa, 2GPa, 5GPa or 10GPa, preferably 1-10GPa, more preferably 2-10GPa.

[0028] In some preferred embodiments, when the inorganic calcium salt is a combination of "calcium carbonate and calcium phosphate", the pressure value of the tabletting is 1-10GPa, more preferably 2-10GPa.

[0029] In the present application, the time of tabletting can be 1-60min, such as 5min or 10min.

[0030] In a third aspect, the present application also provides a use of the above-mentioned pharmaceutical tablet in the preparation of a long-acting controlled-release drug.

[0031] In the present application, the pharmaceutical tablet can be administered subcutaneously for treatment.

[0032] In the present application, the drug can be a drug for treating diabetes or tumors.

[0033] On the basis of common sense in the art, the above-mentioned preferred conditions can be combined arbitrarily, i.e. to obtain each preferred example of the present application.

[0034] The reagents and raw materials used in the present application are commercially available.

[0035] The positive progress effect of the present application is that:

[0036] 1. The medicine tablet provided by the present application is an amorphous medicine tablet, which avoids the crystallization of traditional medicine tablets before release, and is not conducive to the subsequent drug release; the medicine tablet maintains high drug activity, has excellent long-acting release performance, and balances the effectiveness and safety of the medicine, and can exhibit excellent therapeutic effect in the treatment of multiple disease models (such as tumors and diabetes).

[0037] 2. In order to prepare the above-mentioned medicine tablet, the present application first introduces high pressure at the level of GPa into the processing and forming process of the medicine, induces the fusion of amorphous inorganic minerals by applying high pressure, eliminates the discontinuity of the structure of amorphous inorganic minerals, and makes the active medicine uniformly distributed in the medicine tablet. The preparation process of the present application is simple, the preparation time is relatively short (a few minutes), and the cost is low, which provides a new possibility for the molding of various bioactive medicines under high pressure.

[0038] Further, the present application can also avoid the use of excipients by using high pressure, so that the medicine tablet has higher drug activity, especially for protein drugs; by adjusting the composition ratio of inorganic calcium salt, the control of the speed of crystallization kinetics can also be realized, and the release kinetics of the medicine is further precisely controlled.

[0039] 3. The medicine tablet of the present application can be administered by subcutaneous embedding, realizing the effect of single administration and long-term controllable release, greatly reducing the administration frequency, and improving the compliance of patients. BRIEF DESCRIPTION OF DRAWINGS

[0040] Figure 1 Digital photos and scanning electron microscope images of the medicine tablets prepared in Examples 1-5.

[0041] Figure 2 Digital photos of the medicine tablets prepared in Example 6.

[0042] Figure 3 Element distribution graph of uniform distribution of albumin medicine in the medicine tablet prepared in Example 5.

[0043] Figure 4 Crystallinity curve graph of the medicine tablets prepared in Examples 7 and 8.

[0044] Figure 5 Activity detection result graph of IL-2 in the medicine tablet prepared in Example 10.

[0045] Figure 6 Activity detection result graph of glucose oxidase in the medicine tablet prepared in Example 14.

[0046] Figure 7Figure showing the results of the activity test of the insulin in the pharmaceutical tablet prepared in Example 15.

[0047] Figure 8 Figure showing the in vitro release curve of the pharmaceutical in the pharmaceutical tablet prepared in Examples 1-3 and 5.

[0048] Figure 9 Figure showing the in vitro release curve of the pharmaceutical in the pharmaceutical tablet prepared in Examples 9-13.

[0049] Figure 10 Figure showing the IL-2 concentration in the serum of the mice measured over time after the subcutaneous implantation of the tumor area with the pharmaceutical tablet prepared in Example 10.

[0050] Figure 11 Figure showing the IL-2 concentration in the tumor area of the mice measured over time after the subcutaneous implantation of the tumor area with the pharmaceutical tablet prepared in Example 10.

[0051] Figure 12 Figure showing the pictures of the biological tissue sections obtained by staining the subcutaneous tissue with hematoxylin-eosin after the subcutaneous implantation of the tissue with the pharmaceutical tablet prepared in Example 10 for 1 month.

[0052] Figure 13 Figure showing the evaluation of the therapeutic effect of the pharmaceutical tablet prepared in Examples 9-13 on the mice melanoma tumor after the surgical removal of the tumor; wherein, Figure 13 part a shows the relationship between the tumor size and time, Figure 13 part b shows the relationship between the survival rate and time, Figure 13 part c shows the relationship between the body weight of the mice and time. DETAILED DESCRIPTION

[0053] The present application will be further described in the following examples without limiting the present application to the examples described. The experimental methods in the following examples, for which no specific conditions are mentioned, are selected according to the conventional methods and conditions, or according to the instructions of the commercial products.

[0054] The detailed information of the pharmaceuticals used in the following examples is shown in Table 1.

[0055] Table 1

[0056]

[0057] In the examples of the present application, the size of the calcium carbonate powder used is 200 nm; the structural water content of the calcium carbonate powder is 7%, which is obtained by drying the calcium carbonate raw material at 70°C for 12 h.

[0058] In the embodiments of the present application, the size of the calcium phosphate powder used is 50 nm; the structural water content of the calcium phosphate powder is 3%, which is obtained by drying the calcium carbonate raw material at 70°C for 24 h.

[0059] Example 1-5

[0060] An amorphous calcium carbonate / phosphate pharmaceutical tablet is prepared as follows:

[0061] One milligram of albumin, 7.5 milligrams of calcium carbonate powder and 2.5 milligrams of calcium phosphate powder are placed in a mortar and mixed thoroughly. Four groups of the mixed powder are placed in cylindrical stainless steel metal molds with a diameter of 4 mm, and the molds are placed in a mechanical press. The pressure value of the mechanical press is adjusted so that the molds are subjected to a pressure of 0.25 GPa, 0.5 GPa, 1 GPa, 1.5 GPa and 2 GPa, respectively (corresponding to Examples 1-5, respectively), and the molds are maintained at the selected pressure for 5 minutes. Thereafter, the molds are removed from the press, and an amorphous mineral tablet containing albumin is obtained.

[0062] Example 6

[0063] An amorphous calcium carbonate / phosphate pharmaceutical tablet is prepared as follows:

[0064] Thirty micrograms of IL-2, 7.5 milligrams of calcium carbonate powder and 2.5 milligrams of calcium phosphate powder are placed in a mortar and mixed thoroughly. The mixed powder is then placed in a cylindrical stainless steel metal mold with a diameter of 4 mm, and the mold is placed in a mechanical press. The pressure value of the mechanical press is adjusted to 10 GPa, and the mold is maintained at the selected pressure for 10 minutes. Thereafter, the mold is removed from the press, and an amorphous mineral tablet containing IL-2 is obtained.

[0065] Example 7

[0066] An amorphous calcium carbonate / phosphate pharmaceutical tablet is prepared as follows:

[0067] Thirty micrograms of IL-2, 7.5 milligrams of calcium carbonate powder and 2.5 milligrams of calcium phosphate powder are placed in a mortar and mixed thoroughly. The mixed powder is then placed in a cylindrical stainless steel metal mold with a diameter of 4 mm, and the mold is placed in a mechanical press. The pressure value of the mechanical press is adjusted to 10 GPa, and the mold is maintained at the selected pressure for 10 minutes. Thereafter, the mold is removed from the press, and an amorphous mineral tablet containing IL-2 is obtained.

[0068] Example 8

[0069] An amorphous calcium carbonate / phosphate pharmaceutical tablet is prepared as follows:

[0070] 30 micrograms of IL-2 and 10 milligrams of calcium phosphate powder were placed in a mortar and mixed well, and the mixed powder was placed in a cylindrical stainless steel mold with a diameter of 4 millimeters, and the mold was placed in a mechanical press, and the pressure applied to the mold was maintained at 2 GPa for 10 minutes. After that, the mold was removed from the press, and an amorphous mineral tablet containing IL-2 was obtained.

[0071] Examples 9-13

[0072] An amorphous calcium carbonate / calcium phosphate pharmaceutical tablet was prepared as follows:

[0073] 30 micrograms of IL-2 and different mixing ratios of calcium carbonate powder and calcium phosphate powder were placed in a mortar and mixed well. The mixed powder obtained above was placed in a cylindrical stainless steel mold with a diameter of 4 millimeters, and the mold was placed in a mechanical press, and the pressure applied to the mold was adjusted to 2 GPa, and the pressure was maintained for 5 minutes. After that, the mold was removed from the press, and different amorphous mineral tablets containing IL-2 were obtained.

[0074] The mixing ratio of calcium carbonate and calcium phosphate is as follows:

[0075] 100% calcium carbonate group (Example 9): 10 milligrams of calcium carbonate;

[0076] 75% calcium carbonate group (Example 10): 7.5 milligrams of calcium carbonate, 2.5 milligrams of calcium phosphate;

[0077] 50% calcium carbonate group (Example 11): 5 milligrams of calcium carbonate, 5 milligrams of calcium phosphate;

[0078] 25% calcium carbonate group (Example 12): 2.5 milligrams of calcium carbonate, 7.5 milligrams of calcium phosphate;

[0079] 100% calcium phosphate group (Example 13): 10 milligrams of calcium phosphate.

[0080] Example 14

[0081] An amorphous calcium carbonate / calcium phosphate pharmaceutical tablet was prepared as follows:

[0082] 100 micrograms of glucose oxidase, 7.5 milligrams of calcium carbonate powder, and 2.5 milligrams of calcium phosphate powder were placed in a mortar and mixed well, and the mixed powder was placed in a cylindrical stainless steel mold with a diameter of 4 millimeters, and the mold was placed in a mechanical press, and the pressure applied to the mold was adjusted to 2 GPa, and the pressure was maintained for 5 minutes. After that, the mold was removed from the press, and an amorphous mineral tablet containing glucose oxidase was obtained.

[0083] Example 15

[0084] An amorphous calcium carbonate / phosphate drug tablet is prepared by the following method:

[0085] 100 micrograms of insulin, 7.5 milligrams of calcium carbonate powder and 2.5 milligrams of calcium phosphate powder are placed in a mortar and mixed thoroughly and uniformly, and then the mixed powder is placed in a cylindrical stainless steel mold with a diameter of 4 millimeters, and the mold is placed in a mechanical press, and the pressure of the mechanical press is adjusted so that the pressure on the mold is 2 GPa, and the duration is 5 minutes. After that, the mold is taken out of the press, and an amorphous mineral drug tablet containing insulin is obtained.

[0086] Effect Example 1 structure morphology

[0087] Figure 1 The digital photos and scanning electron microscope images of the drug tablets prepared in Examples 1-5 under different external pressures are shown. The results show that the fusion of calcium carbonate and calcium phosphate is induced by the high pressure method of the present application. Specifically, from the digital photos, it can be observed that as the pressure increases, the tablets gradually become optically transparent, which indicates that the prepared tablets not only are simply pressed into tablets, but also have a fusion phenomenon inside. From the scanning electron microscope images, it can be clearly observed that when calcium phosphate and calcium carbonate are used as inorganic minerals, the degree of fusion of the drug tablets is better as the pressure increases, especially under a pressure of 1 GPa or more, and when the pressure reaches 2 GPa, the calcium phosphate and calcium carbonate are completely fused.

[0088] Figure 2 The digital photo of the drug tablet prepared in Example 6 under an external pressure of 10 GPa is shown. The results show that even under a high pressure of 10 GPa, the prepared drug tablet can still maintain an intact state.

[0089] Figure 3 The element distribution map of the albumin drug in the drug tablet prepared in Example 5 is shown. The data points in the picture represent the distribution of N element unique to the albumin drug. The results show that an external pressure of 2 GPa can induce the fusion of amorphous minerals, further promoting the uniform distribution of the albumin drug in the tablet.

[0090] Effect Example 2 crystallization kinetics test

[0091] The drug tablet prepared in Example 7 using calcium carbonate as an inorganic mineral (referred to as calcium carbonate tablet) and the drug tablet prepared in Example 8 using calcium phosphate as an inorganic mineral (referred to as calcium phosphate tablet) are respectively immersed in a PBS buffer, and the immersion time is adjusted, and then the tablets are taken out and dried. The crystallinity of the tablets is characterized by an X-ray diffractometer, and the crystallinity curve of the drug tablet is drawn as shown in Figure 4 Table 2.

[0092] Table 2

[0093]

[0094] Note: " / " means not detected.

[0095] The results show that the crystallinity of the two kinds of drug tablets at the initial time is 0, i.e. the prepared drug tablets are amorphous drug tablets. After soaking in the PBS buffer, the calcium carbonate drug tablets exhibit a faster crystallization kinetics, and the calcium phosphate drug tablets exhibit a slower crystallization kinetics, which matches the crystallization kinetics law of inorganic minerals. It can be judged that the application can realize the excellent effect of controlled release on the basis of meeting the long-acting release by using the crystallization kinetics properties of different inorganic minerals, and selecting the type and amount of inorganic minerals.

[0096] Effect Example 3 Active Drug Activity Test

[0097] (1) IL-2

[0098] The drug activity was detected by using the conventional IL-2 reporter gene method in the field, Figure 5 The IL-2 drug activity detection result graph of the drug tablet prepared in Example 10 is shown in FIG. 2.

[0099] The results show that under the pressure treatment of 2GPa, the activity of IL-2 in the drug tablet is lower than that of the original IL-2, but it can still maintain excellent activity and can be used for subsequent drug treatment research.

[0100] (2) Glucose oxidase

[0101] The activity of glucose oxidase in the drug tablet was determined by using a glucose oxidase activity determination kit. In order to further verify that the drug tablet can maintain the activity of the protein drug for a long time, the drug tablet prepared in Example 14 was stored in a 4℃ refrigerator for half a year, and the activity of glucose oxidase in the drug tablet was determined by using the kit. The activity detection result is shown in FIG. 3. Figure 6

[0102] The results show that the drug tablet prepared in Example 14 can maintain 88% of the original glucose oxidase activity, and even if the drug tablet is stored at 4℃ for half a year, it can still maintain 69% of the original glucose oxidase activity.

[0103] (3) Insulin

[0104] The activity of insulin in the drug tablet was verified by a type I diabetes mouse model. The activity detection result of the drug in the insulin-containing drug tablet prepared in Example 15 is shown in FIG. 4. Figure 7

[0105] ​​The results show that the drug tablet prepared in Example 15 can maintain the original activity of insulin.

[0106] Effect Example 4 Drug in vitro release test

[0107] (1) Albumin

[0108] The drug tablets prepared in Examples 1-3 and Example 5 were respectively soaked in 1 milliliter of PBS buffer solution, and the buffer solution was collected at different release times. The content of the in vitro released albumin was determined by using a BCA protein quantitative test kit, and the drug in vitro release kinetics curve was drawn. The release curve is shown in Figure 8 , and the specific data are shown in Table 3.

[0109] Table 3

[0110]

[0111] The results show that under the high pressure condition of the present application, the longer release performance of the drug is better with the increase of the pressure. When the preparation pressure is less than 0.5 GPa, the albumin drug reaches the highest release point within 2 days; when the preparation pressure is greater than 1 GPa, the release curve of the IL-2 drug is significantly prolonged, and the long-acting stable release of the drug can be achieved at least within 14 days. It can be seen that the higher fusion degree can reduce the rapid release of active drugs in the drug tablet and the occurrence of burst release, and achieve excellent long-term release performance of the drug.

[0112] (2) IL-2

[0113] The drug tablets prepared in Examples 9-13 were respectively soaked in 1 milliliter of PBS buffer solution, and the buffer solution was collected at different release times. The content of the in vitro released IL-2 was determined by using an ELISA test kit of IL-2, and the drug in vitro release kinetics curve was drawn. The release curve is shown in Figure 9 , and the specific data are shown in Table 4.

[0114] Table 4

[0115]

[0116] The results show that by adjusting the different proportions of calcium carbonate and calcium phosphate, the release kinetics of the IL-2 drug can be accurately controlled; among them, the drug tablet prepared in Example 10 containing 75% calcium carbonate shows the best cytokine release kinetics.

[0117] Effect Example 5 Biological tissue compatibility test

[0118] C57BL / 6 mice were inoculated subcutaneously with B16F10 melanoma cells to construct a melanoma tumor-bearing mouse model. The tumors of 99% of the mice were surgically removed to construct a postoperative melanoma resection model. The drug tablets prepared in Example 10 were implanted into the postoperative cavity of the mice as the experimental group (intratumoral embedding of IL-2 tablets), 30 μg of IL-2 solution was injected into the postoperative cavity as the positive control group (intratumoral injection of IL-2 solution), and untreated postoperative mice were used as the negative control group.

[0119] Test method: At different time points, the mice were bled from the eye orbit, and the IL-2 content in the serum was measured. The postoperative tumors were dissected at different time points, and the IL-2 content in the tumor tissue was measured by tissue lysis treatment and an IL-2 ELISA kit. The drug tablets prepared in Example 10 were implanted subcutaneously in healthy mice, and after one month, the subcutaneous skin tissue was removed for hematoxylin-eosin staining to evaluate the biocompatibility of the drug tablets.

[0120] Test results are as follows:

[0121] Figure 10 The drug tablets prepared in Example 10 were implanted subcutaneously in the postoperative region of the tumor, and the IL-2 drug concentration in the serum of the mice was measured. The specific data are shown in Table 5.

[0122] Table 5

[0123]

[0124] The results show that, compared with intratumoral injection of IL-2 solution, intratumoral embedding of IL-2 tablets can significantly reduce the leakage of IL-2 drug into the blood of the mice, thereby achieving high biological safety.

[0125] Figure 11 The drug tablets prepared in Example 10 were implanted subcutaneously in the postoperative region of the tumor, and the IL-2 drug concentration in the serum of the mice was measured. The specific data are shown in Table 5.

[0126] Table 6

[0127]

[0128] The results show that, compared with intratumoral injection of IL-2 drug, intratumoral embedding of IL-2 tablets can achieve long-acting release of IL-2 drug in the local region, and maintain an effective drug concentration for at least two weeks.

[0129] Figure 12Pictures of the biological tissue sections of the subcutaneous tissue stained with hematoxylin-eosin after the drug tablets prepared in Example 10 were implanted into the subcutaneous tissue of mice for 1 month. The results showed that the drug tablets of the present application had long-acting biocompatibility, and even if embedded in the subcutaneous tissue for up to one month, still exhibited good biocompatibility.

[0130] Effect Example 6 Anti-tumor and biological safety test

[0131] C57BL / 6 mice were subcutaneously inoculated with B16F10 melanoma cells to construct a melanoma tumor-bearing mouse model. The tumors of 99% of the mice were surgically removed to construct a postoperative resection model of melanoma.

[0132] Test method: the drug tablets prepared in Examples 9-13 were respectively implanted into the postoperative cavity of the mice, and the size change of the postoperative tumor of the mice was regularly monitored (part a of Figure 13 ), and the survival rate (part b of Figure 13 ) and the change of the body weight of the mice (part c of Figure 13 ) were counted, and the specific data are shown in Table 7.

[0133] Table 7

[0134]

[0135] Note: " / " indicates that the mouse has died.

[0136] The results showed that the drug tablets prepared in Example 10 containing 75% calcium carbonate exhibited the most excellent anti-tumor effect, and had obvious advantages in inhibiting the growth of postoperative tumors and improving the survival rate of tumor-bearing mice, and at the same time could maintain excellent biological safety, and did not cause abnormal changes in the body weight of the mice.

[0137] Although the specific embodiments of the present application are described above, those skilled in the art should understand that these are only illustrative, and various changes or modifications can be made to these embodiments without departing from the principles and essence of the present application. Therefore, the protection scope of the present application is defined by the appended claims.

Claims

1. A pharmaceutical tablet, characterized in that, The drug tablet is an amorphous tablet; the drug tablet comprises inorganic minerals and an active drug; wherein the inorganic minerals are a combination of one or more inorganic calcium salts, and the structural water content of the inorganic minerals is 1-16%; the active drug is a solid, and the content of the active drug is ≤10%, the percentage being the percentage of the active drug by mass of the drug tablet.

2. The pharmaceutical tablet according to claim 1, wherein The drug tablets meet one or more of the following conditions: a. In the drug tablet, the interface between several inorganic mineral particles is an interface fusion; b. The structural water content of the inorganic mineral is 1%, 2%, 3%, 7%, 11%, or 16%; c. The drug tablets do not contain excipients; d. The active pharmaceutical ingredient is selected from one or more of natural drugs, chemically synthesized drugs, and biosynthetic drugs.

3. The pharmaceutical tablet according to claim 1 or 2, characterized in that The inorganic calcium salt is selected from one or more of calcium carbonate, calcium phosphate, calcium oxalate, calcium oxide, calcium chloride, calcium hydrogen phosphate, and calcium manganate, preferably a combination of two, three, four, five, six, or seven inorganic calcium salts, such as a combination of two calcium carbonate and calcium phosphate, a combination of three calcium phosphate, calcium oxalate, and calcium oxide, a combination of three calcium carbonate, calcium phosphate, and calcium manganate, a combination of four calcium carbonate, calcium phosphate, calcium oxide, and calcium hydrogen phosphate, a combination of five calcium carbonate, calcium phosphate, calcium oxide, calcium chloride, and calcium hydrogen phosphate, a combination of six calcium carbonate, calcium phosphate, calcium oxalate, calcium oxide, calcium chloride, and calcium manganate, or a combination of seven calcium carbonate, calcium phosphate, calcium oxalate, calcium oxide, calcium chloride, calcium hydrogen phosphate, and calcium manganate.

4. The pharmaceutical tablet according to claim 3, wherein When the inorganic calcium salt is a combination of calcium carbonate and calcium phosphate, the mass ratio of calcium carbonate to calcium phosphate is 1:3, 1:2, 1:1, 2:1 or 3:

1.

5. The pharmaceutical tablet according to claim 1 or 2, wherein The content of the active pharmaceutical ingredient is 0.000001-10%, for example 0.000001%, 0.00001%, 0.0001%, 0.001%, 0.01%, 0.1%, 0.3%, 1%, 3%, 5% or 10%, preferably 1-10%.

6. The pharmaceutical tablet according to claim 2, wherein The active pharmaceutical ingredient satisfies one or more of the following conditions: a. The natural medicine is selected from traditional Chinese medicine and / or natural herbs, preferably one or more of flavonoids, alkaloids, lignans, coumarins, saponins and cardiac glycosides, such as flavonoids, quercetin, tea polyphenols, hyoscyamine, dicumarol, acetocoumarin, phenylpropanol, digoxin, deslanoside, digitalisin, astragalus, licorice, sophora flavescens, kudzu root, schisandra, psoralea, magnolia bark and scutellaria baicalensis; b. The chemically synthesized drug is selected from one or more of the following: quinolone drugs, sulfonamide drugs, trimethoprim drugs, nitroimidazole drugs, nitrofuran drugs, oxazolidinone drugs, steroid hormone drugs, semi-synthetic antibiotic drugs, nervous system drugs, cardiovascular and cerebrovascular treatment drugs, and chemotherapeutic drugs for malignant tumors, such as one or more of nematamide, ritonavir, monaspirone, azvudine, and methimazole; c. the biosynthetic drug is selected from one or more of the group consisting of cytokine drugs, nucleic acid drugs and protein drugs, such as one or more of recombinant human interleukin 2, albumin, antibodies, glucose oxidase and insulin.

7. A process for the preparation of a pharmaceutical tablet according to any one of claims 1 to 6, characterized in that, The mixture of active drug and inorganic mineral is tabletted, the inorganic mineral having a structural water content of 1-16% prior to tableting, and the tableting being performed at a pressure of 0.1-10 GPa.

8. The production method according to claim 7, wherein The inorganic mineral satisfies one or more of the following conditions: a. the inorganic mineral has a structural water content of 1%, 2%, 3%, 7%, 11% or 16% prior to tableting; b. the inorganic mineral has a particle size of 10-1000 nm, such as 50 nm or 200 nm, prior to tableting.

9. The production method according to claim 7, wherein The tableting step satisfies one or more of the following conditions: a. the tableting is performed at a pressure of 0.1 GPa, 0.25 GPa, 0.5 GPa, 0.76 GPa, 1 GPa, 1.2 GPa, 1.5 GPa, 2 GPa, 5 GPa or 10 GPa, preferably 1-10 GPa, more preferably 2-10 GPa; b. the tableting is performed for a time of 1-60 min, such as 5 min or 10 min.

10. Use of a pharmaceutical tablet according to any one of claims 1-6 for the preparation of a long-acting, controlled release pharmaceutical.

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