CN108578371B - Streptomycin calcium sulfate sustained release preparation and preparation method thereof - Google Patents
Streptomycin calcium sulfate sustained release preparation and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the field of sustained-release medicines, and particularly relates to a streptomycin calcium sulfate sustained-release preparation which comprises, by weight, 0.5-9 parts of streptomycin sulfate, 2.6-21 parts of calcium sulfate, 1-9 parts of sterile water for injection, and also comprises 2.6-5 parts of glycosaminoglycan and 2.6-5 parts of bone peptide. The preparation is granules with the diameter less than or equal to 4mm, and is composed of an inner release layer, a middle release layer and an outer release layer which are tightly connected in sequence from inside to outside. The streptomycin calcium sulfate sustained-release preparation is prepared at low temperature, and has better effect. The invention combines streptomycin sulfate and calcium sulfate to form a drug delivery system, replaces the existing intramuscular injection drug delivery mode and multilayer design, particularly sequentially releases bone peptide and glycosaminoglycan in the process of anti-bone tuberculosis early strengthening treatment, promotes the beneficial effect of bone rapid repair, and solves the problems of pain and inconvenience caused by too low local drug concentration, bacterial drug resistance, insufficient or too slow dietary nutrition supplement, intramuscular injection and other modes.
Description
Technical Field
The invention belongs to the field of sustained-release medicines, and particularly relates to a streptomycin calcium sulfate sustained-release preparation and a preparation method thereof.
Background
Tuberculosis mostly occurs in the lungs, but can also occur in any organ of the human body. About 50% of patients with bone tuberculosis are combined with pulmonary tuberculosis, tuberculosis sclerotium firstly occurs in the lung, and after lung infection, the tuberculosis can be transmitted to a plurality of systems of the whole body through blood, and can cause bone tuberculosis, urinary tuberculosis, digestive tuberculosis and the like. In this case, bone tuberculosis is not a simple disease, but a local manifestation of systemic disease. Patients with bone tuberculosis may also have no history of tuberculosis and are insidious infections with tubercle bacillus. Osteoarticular tuberculosis is one of the most common extrapulmonary tuberculosis, and the incidence of tuberculosis is in a remarkable trend in recent years. If the diagnosis and treatment of the osteoarticular tuberculosis are not timely or normative, the joint is easily damaged or the vertebral canal is easily affected, and the spinal nerves are pressed to cause paralysis.
Streptomycin sulfate is an aminoglycoside antibiotic and has a strong antibacterial effect on tubercle bacillus. The general administration modes include oral administration and intramuscular injection, while the oral administration of the streptomycin sulfate can not be absorbed, but the intramuscular injection has good absorption, is mainly distributed in extracellular fluid, can reach tuberculous abscess, cheese-like tissues and exudates, has strong bactericidal effect on extracellular tubercle bacillus, is a first-line antitubercular medicament, and is widely applied to clinic.
The intramuscular administration of streptomycin has the following disadvantages: due to the particularity of tuberculosis resistance, streptomycin usually needs to be injected into muscles continuously for 3 months, and a plurality of patients are difficult to persist; secondly, long-term intramuscular injection easily causes complications such as injection site infection, induration, muscle contracture and the like, and forces the treatment to be interrupted; and long-term application of streptomycin can cause renal toxicity and ototoxicity, and the toxicity is closely related to blood concentration of streptomycin. Once nephrotoxicity and/or ototoxicity occurs, streptomycin administration must be suspended, thereby affecting the efficacy of tuberculosis treatment.
At present, tuberculosis surgery, especially bone tuberculosis surgery, usually sprays streptomycin sulfate powder on the wound surface after removing tuberculosis focus, but the administration mode has the following disadvantages: firstly, early wound surface tissues after a focus clearing operation are in an edema exudation stage and a bleeding stage, most of streptomycin is dissolved along with the exudation liquid and the blood and is discharged out of a body through a drainage tube, and the streptomycin is absorbed into the blood and distributed on the whole body after the focus wound surface tissues are converted into an absorption stage after the drainage tube is pulled out, so that the local medicine concentration is reduced, and the effective medicine concentration maintenance time is not long enough; ② if excessive medicine is given in the focus at one time, although the local concentration and effective acting time of the medicine can be improved, the occurrence rate of adverse reaction of the medicine is increased when the blood medicine concentration is too high after the excessive medicine is absorbed into the blood.
Disclosure of Invention
In order to solve the technical problems, the invention provides a streptomycin calcium sulfate sustained release preparation, which combines streptomycin sulfate and calcium sulfate to form a drug delivery system, replaces the intramuscular injection drug delivery mode in the prior art, is placed at the tuberculosis affected part in an operation, such as in bone marrow, takes calcium sulfate as a skeleton carrier, enriches and slowly releases the streptomycin sulfate, and exerts long-term, continuous and effective drug concentration to achieve the purpose of treating tuberculosis, particularly bone tuberculosis. The calcium sulfate skeleton is gradually degraded, calcium ions are absorbed, and the calcium sulfate is used as a nutrient substance, particularly promotes the repair of bone defect positions, and has no side effect.
The invention also aims to provide a preparation method of the streptomycin calcium sulfate sustained-release granules.
The technical scheme of the invention is as follows:
a streptomycin calcium sulfate sustained release preparation comprises, by weight, 0.5-9 parts of streptomycin sulfate, 2.6-21 parts of calcium sulfate and 1-9 parts of sterile water for injection.
In the preferable technical scheme, the streptomycin calcium sulfate sustained-release preparation comprises, by weight, 0.5-3 parts of streptomycin sulfate, 2.6-7 parts of calcium sulfate and 1-3 parts of sterile water for injection.
In the preferable technical scheme of the invention, the streptomycin calcium sulfate sustained-release preparation further comprises 2.6-5 parts by weight of glycosaminoglycan and 2.6-5 parts by weight of bone peptide.
In the preferred technical scheme of the invention, the streptomycin calcium sulfate sustained-release preparation is granules with the diameter less than or equal to 4 mm.
In a preferred technical scheme of the invention, the particles comprise an inner release layer, a middle release layer and an outer release layer which are tightly connected in sequence from inside to outside, and the particles are in a cylindrical structure, a spherical structure or a spiral structure.
In a preferred technical scheme of the invention, the outer release layer mainly comprises the calcium sulfate, the streptomycin sulfate and the sterile water for injection, the middle release layer mainly comprises the bone peptide, the calcium sulfate, the streptomycin sulfate and the sterile water for injection, and the inner release layer mainly comprises the glycosaminoglycan, the calcium sulfate, the streptomycin sulfate and the sterile water for injection.
In the preferable technical scheme of the invention, the outer release layer mainly comprises the following components, by weight, 0.5-3 parts of streptomycin sulfate, 2.6-7 parts of calcium sulfate and 1-3 parts of sterilized water for injection; the middle release layer mainly comprises the following components, by weight, 2.6-5 parts of bone peptide, 2.6-7 parts of calcium sulfate, 0.5-3 parts of streptomycin sulfate and 1-3 parts of sterilized water for injection; the inner release layer mainly comprises the following components, by weight, 2.6-5 parts of glycosaminoglycan, 2.6-7 parts of calcium sulfate, 0.5-3 parts of streptomycin sulfate and 1-3 parts of sterile water for injection.
The invention provides a preparation method of streptomycin calcium sulfate sustained release preparation, which comprises the following steps,
s1: placing streptomycin sulfate powder and calcium sulfate powder in corresponding weight parts in a sterile environment, and uniformly stirring;
s2: adding corresponding parts by weight of sterilized water for injection; fully stirring for 20-40 seconds at low temperature until the paste is uniform and pasty;
s3: uniformly coating paste on the mould with the corresponding shape; pressurizing and driving the residual air by using the pressure of 15-20N;
s4: standing the paste in a mold for more than 10 minutes for curing;
s5: the telescopic mould releases the granules;
s6: sterilizing the prepared granules, and storing at low temperature for later use;
the low-temperature stirring and mixing temperature is 0-5 ℃, and the standing time in the die is 2-4 ℃ of low-temperature storage temperature.
The preparation method of the other streptomycin calcium sulfate sustained-release drug delivery system preparation provided by the invention comprises the following steps,
s1, placing streptomycin sulfate powder and calcium sulfate powder in corresponding weight parts in a sterile environment, and uniformly stirring;
s2, adding corresponding parts by weight of sterilized water for injection, fully stirring for 20-40 seconds at low temperature until the paste is uniform and pasty, dividing into three parts, wherein one part is used as external release slurry for later use, the other part is added with corresponding parts by weight of glycosaminoglycan to obtain inner layer slurry for later use, and the other part is added with corresponding parts by weight of bone peptide to obtain middle layer slurry for later use;
s3, uniformly coating inner release layer slurry on an inner release layer mould with a corresponding shape, pressurizing with the pressure of 15-20N to drive the residual air, standing for 10-15 minutes to cure to obtain an inner release layer;
s4, fixing the inner release layer in the center of the middle release layer mold, uniformly coating middle layer slurry at the position of the gap, pressurizing by using the pressure of 15-20N to drive the residual air, standing for 10-15 minutes and curing to obtain a mixed layer;
s5, fixing the mixed layer in the center of an outer layer die, uniformly coating outer layer slurry at the position of a gap, pressurizing by using the pressure of 15-20N to drive the residual air, standing for more than 10 minutes to solidify to obtain a preparation, and storing at low temperature for later use;
the low-temperature stirring and mixing temperature is 0-5 ℃, and the standing time in the die is 2-4 ℃ of low-temperature storage temperature.
The streptomycin calcium sulfate sustained-release preparation for treating bone tuberculosis provided by the invention is applied to bone marrow in bone tuberculosis surgical treatment.
Compared with the prior art, the invention has the beneficial effects that:
1. the calcium sulfate is used as a drug carrier, can be completely absorbed in organisms, has better biocompatibility and formability, and can form physiological combination with tissues, particularly original bone tissues after being implanted.
2. The streptomycin calcium sulfate sustained-release preparation is used for treating bone tuberculosis, and simultaneously can provide a support for new bone growth, fill bone defects and prevent surrounding soft tissues from growing in quickly; after degradation, a large amount of calcium ions are provided, the activity of osteoblasts is stimulated, and osteogenesis is induced;
3. the streptomycin calcium sulfate sustained-release preparation is convenient to sterilize, and can be quickly applied to the body only by carrying out conventional operation ultraviolet sterilization before treatment.
4. The medicine of the present invention is enriched in tuberculosis parts, such as bone marrow, and has long half life, no toxic side effect and high treating effect.
5. According to the invention, by embedding the slow release system in the operative region, the calcium sulfate stent is gradually degraded and absorbed, the streptomycin concentration of the wound surface of the bone tuberculosis is kept at the effective bactericidal drug concentration for a long time, and meanwhile, the bone defect position is gradually repaired, so that the slow release bone tuberculosis repair device has an important clinical application value for realizing the thorough treatment of the bone tuberculosis. The preparation of the granule not only avoids the defect of local intramuscular injection, but also can achieve the purpose of long-term slow-release effective concentration of medication and anti-tuberculosis.
6. The preparation method provided by the invention provides possibility for realizing industrialization of the streptomycin calcium sulfate sustained-release preparation, the cost is low, and the prepared preparation can be stored at low temperature and used after ultraviolet sterilization before operation. The preparation is inconvenient during operation, the component standards are not uniform, the proportion of each component is inaccurate, or the slow-release concentration of the medicine is too low, so that the medicine effect is damaged, or the slow-release concentration of the medicine is too high, the slow-release time is too short, and the purpose of treating tuberculosis cannot be achieved.
7. The preparation method of the invention can achieve the most effective slow-release effect only by placing the streptomycin sulfate and the calcium sulfate in a low-temperature environment for fusion adsorption.
8. Due to the multi-layer design, after the primary inflammation diminishing of the bone tuberculosis, in the process of continuing to diminish inflammation, the bone peptide and the glycosaminoglycan are sequentially released, the beneficial effect of promoting the rapid repair of bones is achieved, and the problems of pain and inconvenience caused by too low local drug concentration, bacterial drug resistance, insufficient or too slow dietary nutrition supplement, intramuscular injection and other modes are solved.
Drawings
FIG. 1: example 3 group (group a 3) blood concentration profile;
FIG. 2: example 3 group (group a 3) tissue metabolic concentration curve;
FIG. 3: control group blood concentration profile;
FIG. 4: control group tissue metabolic concentration curve
FIG. 5: example 3 group (group a 3) post-operative two week renal HE staining profile;
FIG. 6: example 3 group (group a 3) eight weeks post-operative renal HE staining profile;
FIG. 7: example 3 group (group a 3) HE staining pattern of liver two weeks after surgery;
FIG. 8: example 3 group (group a 3) HE staining pattern of liver eight weeks post-surgery;
FIG. 9: schematic of an embodiment of the formulation of the invention in cylindrical form;
FIG. 10: FIG. 9 is a cross-sectional view;
FIG. 11: the formulation of the present invention is illustrated as a spiral in the examples.
Reference numerals: 1-external release layer, 2-intermediate release layer and 3-internal release layer.
Detailed Description
The following examples are provided to illustrate specific embodiments of the present invention.
A streptomycin calcium sulfate sustained release preparation comprises, by weight, 0.5-9 parts of streptomycin sulfate, 2.6-21 parts of calcium sulfate and 1-9 parts of sterile water for injection.
The calcium sulfate is used, wherein medical grade calcium sulfate is used, the calcium sulfate is a good bone repair filling material, has the characteristics of various ideal bone graft substitute materials, has a good adsorption effect with streptomycin sulfate, has a good slow release effect, and is particularly suitable for bone tuberculosis surgeries. But not only the application to the bone tuberculosis, but also the application to other tuberculosis.
Preferably, the streptomycin calcium sulfate sustained-release preparation comprises, by weight, 0.5-3 parts of streptomycin sulfate, 2.6-7 parts of calcium sulfate and 1-3 parts of sterile water for injection. When the weight ratio of the streptomycin sulfate to the calcium sulfate is 1: 5, particularly when the weight ratio of the streptomycin sulfate to the calcium sulfate is 1g and the weight ratio of the calcium sulfate to the calcium sulfate is 5g, the prepared preparation particles can last for a long time and are not easy to break, the treatment effect is best, and the relapse is not easy to occur.
Preferably, the bone peptide also comprises 2.6-5 parts of glycosaminoglycan and 2.6-5 parts of bone peptide.
The streptomycin calcium sulfate sustained-release preparation is granules, and the diameter of the granules is not more than 4 mm. The diameter and the height of the bottom surface are not more than 4mm, preferably 2mm and 3 mm; the particles are of cylindrical structures, spherical structures or spiral structures, the structure of the preparation is designed to be more adaptive to the structure of a human body, as shown in fig. 9 and 10, the cylindrical structures are adaptive to the longitudinal structure of bones, so that the medicine is uniformly released in the bones along the longitudinal direction of the bones, the release area of the medicine is uniformly expanded, meanwhile, the medicine is prevented from being excessively enriched, the metabolic flow of bone fluid is prevented, and the preparation is suitable for areas with larger bone core areas. The spherical structure is suitable for the area with small bone tuberculosis area or other muscle tissues, concentrated release is realized, and the spherical structure is generally small. As shown in fig. 11, the spiral structure acts like a cylindrical structure, and is more suitable for the cases of bone tuberculosis or other tissue organ tuberculosis with long longitudinal extension and small transverse tuberculosis compared with the cylindrical structure, and is also suitable for the special bending places such as bone joints.
Preferably, the particles comprise an inner release layer 3, an intermediate release layer 2 and an outer release layer 1 which are tightly connected in sequence from inside to outside, wherein the outer release layer 1 is mainly prepared from the calcium sulfate, the streptomycin sulfate and the sterilized water for injection, the intermediate release layer 2 is mainly prepared from the bone peptide, the calcium sulfate, the streptomycin sulfate and the sterilized water for injection, and the inner release layer 3 is mainly prepared from the glycosaminoglycan, the calcium sulfate, the streptomycin sulfate and the sterilized water for injection.
The bone peptide and glycosaminoglycan are nutrients required for bone or bone marrow repair, and other required nutrients or other medicines can be replaced according to needs.
Preferably, the outer release layer 1 mainly comprises the following components, by weight, 0.5-3 parts of streptomycin sulfate, 2.6-7 parts of calcium sulfate and 1-3 parts of sterilized water for injection; the middle release layer 2 mainly comprises the following components, by weight, 2.6-5 parts of bone peptide, 2.6-7 parts of calcium sulfate, 0.5-3 parts of streptomycin sulfate and 1-3 parts of sterilized water for injection; the inner release layer 3 mainly comprises the following components, by weight, 2.6-5 parts of glycosaminoglycan, 2.6-7 parts of calcium sulfate, 0.5-3 parts of streptomycin sulfate and 1-3 parts of sterile water for injection. The design of the multi-layer structure can be used for adding different substances according to the nutritional requirements or the requirements of treating diseases.
The invention relates to a method for preparing streptomycin calcium sulfate sustained release preparation, which comprises the following steps,
s1: placing streptomycin sulfate powder and calcium sulfate powder in corresponding weight parts in a sterile environment, and uniformly stirring;
s2: adding corresponding parts by weight of sterilized water for injection; fully stirring for 20-40 seconds at low temperature until the paste is uniform and pasty;
s3: uniformly coating paste on the mould with the corresponding shape; pressurizing and driving the residual air by using the pressure of 15-20N;
s4: standing the paste in a mold for more than 10 minutes for curing;
s5: the telescopic mould releases the granules;
s6: sterilizing the prepared granules, and storing at low temperature for later use;
the low-temperature stirring and mixing temperature is 0-5 ℃, the preferred low-temperature stirring and mixing temperature is 2-4 ℃, the optimal value is 3 ℃, and the standing time in the die is 2-4 ℃ of the low-temperature storage temperature.
Preferably, the low-temperature stirring time is 25-35 seconds, the pressurizing pressure is 17-20N, the standing time in the mold is 10-30 minutes, and the low-temperature storage temperature is 1-4 ℃.
Preferably, the low-temperature stirring time is 27-32 seconds, the pressurizing pressure is 18-20N, the standing time in the mold is 10-30 minutes, and the low-temperature storage temperature is 3-4 ℃.
It is preferable that the low-temperature stirring time is 30 seconds, the pressurizing pressure is 20N, the time for standing in the mold is 15 minutes, and the low-temperature storage temperature is 4 ℃.
The sustained-release preparation prepared by the method takes calcium sulfate as a carrier, slowly releases streptomycin sulfate, and has the main function of resisting bacteria and treating tuberculosis.
The other preparation method of the streptomycin calcium sulfate sustained-release preparation comprises the following steps,
s1, placing streptomycin sulfate powder and calcium sulfate powder in corresponding weight parts in a sterile environment, and uniformly stirring;
s2, adding corresponding parts by weight of sterilized water for injection, fully stirring for 20-40 seconds at low temperature until the paste is uniform and pasty, dividing into three parts, wherein one part is used as external release slurry for later use, the other part is added with corresponding parts by weight of glycosaminoglycan to obtain inner layer slurry for later use, and the other part is added with corresponding parts by weight of bone peptide to obtain middle layer slurry for later use;
s3, uniformly coating the inner release layer 3 slurry on an inner release layer 3 mould with a corresponding shape, pressurizing and driving the residual air by using the pressure of 15-20N, standing for 10-15 minutes and curing to obtain an inner release layer 3;
s4, fixing the inner release layer 3 in the center of the mold of the middle release layer 2, uniformly coating middle layer slurry at the position of the gap, pressurizing by using the pressure of 15-20N to drive the residual air, standing for 10-15 minutes and curing to obtain a mixed layer;
s5, fixing the mixed layer in the center of an outer layer die, uniformly coating outer layer slurry at the position of a gap, pressurizing by using the pressure of 15-20N to drive the residual air, standing for more than 10 minutes to solidify to obtain a preparation, and storing at low temperature for later use;
the streptomycin calcium sulfate sustained-release preparation is prepared by the method, but is not limited to the method, and the preparation method is different according to different moulds. The preparation method of the invention achieves the purpose of layer-by-layer wrapping according to the corresponding inner release layer 3 mould, the middle release layer 2 mould and the outer release layer 1 mould. The inner release layer 3 mould, the middle release layer 2 mould and the outer release layer 1 mould are respectively moulds with the same shape and different sizes, wherein the outer release layer 1 mould is proportionally larger than the middle release layer 2 mould, and sequentially, the middle release layer 2 mould is proportionally larger than the inner release layer 3 mould,
the low-temperature stirring and mixing temperature is 0-5 ℃, and the standing time in the die is 2-4 ℃ of low-temperature storage temperature.
Wherein the low-temperature stirring and mixing temperature is 0-5 ℃, the preferred low-temperature stirring and mixing temperature is 2-4 ℃, the optimal value is 3 ℃, and the standing time in the die is 2-4 ℃ of the low-temperature storage temperature.
Preferably, the low-temperature stirring time is 25-35 seconds, the pressurizing pressure is 17-20N, and the low-temperature storage temperature is 1-4 ℃.
Preferably, the low-temperature stirring time is 27-32 seconds, the pressurizing pressure is 18-20N, and the low-temperature storage temperature is 3-4 ℃.
It is preferable that the low-temperature stirring time is 30 seconds, the pressurizing pressure is 20N, the time for standing in the mold is 15 minutes, and the low-temperature storage temperature is 4 ℃.
The preparation prepared according to the above method is a multi-layered preparation, and the preparation method of the multi-layered preparation is not limited to the above method.
The streptomycin calcium sulfate sustained-release drug delivery system preparation is applied to bone marrow placement in bone tuberculosis surgical treatment.
The streptomycin sulfate is streptomycin sulfate for injection, and the calcium sulfate is medical calcium sulfate.
The following examples are provided to illustrate the present invention in more detail:
the streptomycin calcium sulfate sustained release preparation has a single-layer cylindrical granule, the diameter and height of the bottom surface of the granule are both not more than 4mm, and the diameter and height of the bottom surface are preferably 2mm or 3mm,
example 1
A streptomycin calcium sulfate sustained release preparation is mainly prepared from 0.5g streptomycin sulfate, 2.6g calcium sulfate, and 1g sterilized water for injection; the specific method is as follows,
placing the streptomycin sulfate powder and calcium sulfate powder in an aseptic environment, and uniformly stirring; adding the sterilized water for injection in parts by weight; fully stirring for 20 seconds at the temperature of 0 ℃ until the paste is uniform, uniformly coating the paste on a cylindrical porous mould, and filling the pores; pressurizing and driving the residual air by using the pressure of 15N; standing the paste in a mould for 10 minutes for curing; the telescopic mould releases the granules; and storing at 2 deg.c for further use.
The prepared preparation is refrigerated at low temperature, and the preparation and other operation medicines are placed under an ultraviolet lamp for conventional sterilization during operation, so that the preparation can be placed in bone marrow at the affected part of a bone tuberculosis patient during operation; because calcium sulfate is not easy to dissolve in water, the calcium sulfate can be completely dissolved in bone marrow after a month, and the streptomycin sulfate is slowly released along with the calcium sulfate and dissolved in the bone marrow to play a therapeutic role.
The streptomycin sulfate is streptomycin sulfate for injection, and the calcium sulfate is medical calcium sulfate.
Example 2
A streptomycin calcium sulfate sustained release preparation is mainly prepared from 3g streptomycin sulfate, 7g calcium sulfate and 3g sterilized water for injection, and the preparation method comprises the following steps,
placing the streptomycin sulfate powder and calcium sulfate powder in an aseptic environment, and uniformly stirring; adding the sterilized water for injection; fully stirring for 40 seconds in a low-temperature environment until the paste is uniform and pasty, wherein the temperature for stirring and mixing at low temperature is 5 ℃; uniformly coating paste on the cylindrical porous die and filling the pores with the paste; pressurizing and driving the residual air by using the pressure of 20N; standing the paste in a mold for 30 minutes for curing; the telescopic mould releases the granules; and storing at 3 deg.c for further use.
The prepared preparation is refrigerated at low temperature, and the preparation and other operation medicines are placed under an ultraviolet lamp for conventional sterilization during operation, so that the preparation can be placed in bone marrow at the affected part of a bone tuberculosis patient during operation; because calcium sulfate is not easy to dissolve in water, the calcium sulfate can be completely dissolved in bone marrow after a month, and the streptomycin sulfate is slowly released along with the calcium sulfate and dissolved in the bone marrow to play a therapeutic role.
The streptomycin sulfate is streptomycin sulfate for injection, and the calcium sulfate is medical calcium sulfate.
Example 3
A streptomycin calcium sulfate sustained release preparation is mainly prepared from 1g streptomycin sulfate, 5g calcium sulfate and 2g sterilized water for injection, and comprises the following steps,
placing the streptomycin sulfate powder and calcium sulfate powder in an aseptic environment, and uniformly stirring; adding the sterilized water for injection; fully stirring for 30 seconds in a low-temperature environment until the paste is uniform and pasty, wherein the low-temperature stirring and mixing temperature is 3 ℃; uniformly coating paste on the cylindrical porous die and filling the pores with the paste; pressurizing and driving the residual air by using the pressure of 20N; standing the paste in a mould for 15 minutes for curing; the telescopic mould releases the granules; and storing at 4 deg.c for further use.
The prepared preparation is refrigerated at low temperature, and the preparation and other operation medicines are placed under an ultraviolet lamp for conventional sterilization during operation, so that the preparation can be placed in bone marrow at the affected part of a bone tuberculosis patient during operation; because calcium sulfate is not easy to dissolve in water, the calcium sulfate can be completely dissolved in bone marrow after a month, and the streptomycin sulfate is slowly released along with the calcium sulfate and dissolved in the bone marrow to play a therapeutic role.
The streptomycin sulfate is streptomycin sulfate for injection, and the calcium sulfate is medical calcium sulfate.
Example 4
A streptomycin calcium sulfate sustained release preparation is mainly prepared from 1.5g streptomycin sulfate, 4g calcium sulfate and 2g sterilized water for injection, and comprises the following steps,
placing the streptomycin sulfate powder and calcium sulfate powder in an aseptic environment, and uniformly stirring; adding the sterilized water for injection; fully stirring for 35 seconds in a low-temperature environment until the paste is uniform and pasty, wherein the low-temperature stirring and mixing temperature is 5 ℃; uniformly coating paste on the cylindrical porous die and filling the pores with the paste; pressurizing and driving out the residual air by using the pressure of 18N; standing the paste in a mould for 15 minutes for curing; the telescopic mould releases the granules; and storing at 3 deg.c for further use.
The prepared preparation is refrigerated at low temperature, and the preparation and other operation medicines are placed under an ultraviolet lamp for conventional sterilization during operation, so that the preparation can be placed in bone marrow at the affected part of a bone tuberculosis patient during operation; because calcium sulfate is not easy to dissolve in water, the calcium sulfate can be completely dissolved in bone marrow after a month, and the streptomycin sulfate is slowly released along with the calcium sulfate and dissolved in the bone marrow to play a therapeutic role.
The streptomycin sulfate is streptomycin sulfate for injection, and the calcium sulfate is medical calcium sulfate.
Example 5
A streptomycin calcium sulfate sustained release preparation is mainly prepared from 2.5g streptomycin sulfate, 3g calcium sulfate and 1g sterilized water for injection, and comprises the following steps,
placing the streptomycin sulfate powder and calcium sulfate powder in an aseptic environment, and uniformly stirring; adding the sterilized water for injection; fully stirring for 32 seconds in a low-temperature environment until the paste is uniform and pasty, wherein the temperature for stirring and mixing at low temperature is 4 ℃; uniformly coating paste on the cylindrical porous die and filling the pores with the paste; pressurizing and driving the residual air by 17N; standing the paste in a mold for 25 minutes for curing; the telescopic mould releases the granules; and storing at 3.8 deg.c for further use.
The prepared preparation is refrigerated at low temperature, and the preparation and other operation medicines are placed under an ultraviolet lamp for conventional sterilization during operation, so that the preparation can be placed in bone marrow at the affected part of a bone tuberculosis patient during operation; because calcium sulfate is not easy to dissolve in water, the calcium sulfate can be completely dissolved in bone marrow after a month, and the streptomycin sulfate is slowly released along with the calcium sulfate and dissolved in the bone marrow to play a therapeutic role.
The streptomycin sulfate is streptomycin sulfate for injection, and the calcium sulfate is medical calcium sulfate.
Example 6
A streptomycin calcium sulfate sustained release preparation is mainly prepared from 2g streptomycin sulfate, 6g calcium sulfate and 1.7g sterilized water for injection, and comprises the following steps,
placing the streptomycin sulfate powder and calcium sulfate powder in an aseptic environment, and uniformly stirring; adding the sterilized water for injection; fully stirring for 27 seconds in a low-temperature environment until the paste is uniform and pasty, wherein the temperature for stirring and mixing at low temperature is 0 ℃; uniformly coating paste on the cylindrical porous die and filling the pores with the paste; pressurizing and driving the residual air by 16N; standing the paste in a mold for 20 minutes for curing; the telescopic mould releases the granules; and storing at 4 deg.c for further use.
The prepared preparation is refrigerated at low temperature, and the preparation and other operation medicines are placed under an ultraviolet lamp for conventional sterilization during operation, so that the preparation can be placed in bone marrow at the affected part of a bone tuberculosis patient during operation; because calcium sulfate is not easy to dissolve in water, the calcium sulfate can be completely dissolved in bone marrow after a month, and the streptomycin sulfate is slowly released along with the calcium sulfate and dissolved in the bone marrow to play a therapeutic role.
The streptomycin sulfate is streptomycin sulfate for injection, and the calcium sulfate is medical calcium sulfate.
The streptomycin calcium sulfate sustained release preparation has a multi-layer cylindrical granule, the diameter and height of the bottom surface of the granule are both not more than 4mm, and the diameter and height of the bottom surface are preferably 2mm or 3mm,
example 7
A streptomycin calcium sulfate sustained release preparation comprises an inner release layer 3, a middle release layer 2 and an outer release layer 1 which are sequentially and tightly connected from inside to outside; the outer release layer 1 is mainly prepared from the following components, by weight, 0.3g of streptomycin sulfate, 1.5g of calcium sulfate and 0.6g of sterilized water for injection; the middle release layer 2 is mainly prepared from the following components in parts by weight, 1.5g of bone peptide, 1.5g of calcium sulfate, 0.3g of streptomycin sulfate and 0.6g of sterilized water for injection; the inner release layer 3 is mainly prepared from the following components, by weight, 0.6g of glycosaminoglycan, 1.5g of calcium sulfate, 0.3g of streptomycin sulfate and 0.6g of sterilized water for injection.
The method comprises the following specific steps of placing the streptomycin sulfate powder and calcium sulfate powder in an aseptic environment, and uniformly stirring; adding the sterilized water for injection according to the weight, fully stirring for 30 seconds in a low-temperature environment until the mixture is uniform paste, stirring and mixing at a low temperature of 3 ℃, dividing into three parts, wherein one part is used as an external release slurry for later use, the glycosaminoglycan according to the weight is added into one part to obtain an inner layer slurry, uniformly stirring the inner layer slurry for later use, and the bone peptide according to the weight is added into one part to obtain a middle layer slurry, and uniformly stirring the middle layer slurry for later use; uniformly coating the slurry of the inner release layer 3 on a cylindrical inner release layer 3 mould, pressurizing by using the pressure of 20N to drive the residual air, standing for 15 minutes and curing to obtain the inner release layer 3; fixing the inner release layer 3 in the center of the mold of the middle release layer 2, uniformly coating middle layer slurry at the position of the gap, pressurizing by using the pressure of 20N to drive the residual air, standing for 15 minutes and curing to obtain a mixed layer; fixing the mixed layer in the center of the outer layer mold, uniformly coating outer layer slurry in the gap position, pressurizing with 20N pressure to drive out the residual air, standing for more than 15 minutes to solidify to obtain the preparation, and storing at 4 ℃ for later use.
Example 8
A streptomycin calcium sulfate sustained release preparation comprises an inner release layer 3, a middle release layer 2 and an outer release layer 1 which are sequentially and tightly connected from inside to outside; the outer release layer 1 is mainly prepared from the following components, by weight, 0.15g of streptomycin sulfate, 2.1g of calcium sulfate and 0.9g of sterilized water for injection; the middle release layer 2 is mainly prepared from the following components in parts by weight, 2.1g of bone peptide, 0.78g of calcium sulfate, 0.9g of streptomycin sulfate and 0.3g of sterilized water for injection; the inner release layer 3 is mainly prepared from the following components, by weight, 1.5g of glycosaminoglycan, 0.78g of calcium sulfate, 0.9g of streptomycin sulfate and 0.3g of sterilized water for injection.
The method comprises the following specific steps of placing the streptomycin sulfate powder and calcium sulfate powder in an aseptic environment, and uniformly stirring; adding the sterilized water for injection, stirring at low temperature for 20 s to obtain uniform paste, stirring at low temperature and mixing at 5 deg.C, dividing into three parts, one part as external release slurry, one part as internal layer slurry, and one part as bone peptide to obtain middle layer slurry; uniformly coating the inner release layer 3 slurry on a mold with the cylindrical inner release layer 3, pressurizing by using 15N pressure to drive residual air, standing for 13 minutes and curing to obtain the inner release layer 3; fixing the inner release layer 3 in the center of the mold of the middle release layer 2, uniformly coating middle layer slurry at the position of the gap, pressurizing by using the pressure of 15N to drive the residual air, standing for 13 minutes and curing to obtain a mixed layer; fixing the mixed layer in the center of the outer layer mold, uniformly coating outer layer slurry in the gap position, pressurizing with 15N pressure to drive out the residual air, standing for more than 30 minutes to solidify to obtain the preparation, and storing at 0 deg.C for later use.
Example 9
A streptomycin calcium sulfate sustained release preparation comprises an inner release layer 3, a middle release layer 2 and an outer release layer 1 which are sequentially and tightly connected from inside to outside; the outer release layer 1 is mainly prepared from the following components, by weight, 0.9g of streptomycin sulfate, 0.78g of calcium sulfate and 0.3g of sterilized water for injection; the middle release layer 2 is mainly prepared from the following components, by weight, 0.78g of bone peptide, 2.1g of calcium sulfate, 0.15g of streptomycin sulfate and 0.9g of sterilized water for injection; the inner release layer 3 is mainly prepared from the following components, by weight, 0.78g of glycosaminoglycan, 2.1g of calcium sulfate, 0.15g of streptomycin sulfate and 0.3g of sterile water for injection.
The method comprises the following specific steps of placing the streptomycin sulfate powder and calcium sulfate powder in an aseptic environment, and uniformly stirring; adding the sterilized water for injection, stirring at low temperature for 40 s to obtain uniform paste, stirring at low temperature at 0 deg.C, dividing into three parts, one part as external release slurry, one part as internal layer slurry, and one part as bone peptide to obtain middle layer slurry; uniformly coating the inner release layer 3 slurry on a mold with the cylindrical inner release layer 3, pressurizing by 17N to drive residual air, standing for 10 minutes and curing to obtain the inner release layer 3; fixing the inner release layer 3 in the center of the mold of the middle release layer 2, uniformly coating middle layer slurry at the position of the gap, pressurizing by 17N to drive the residual air, standing for 10 minutes and curing to obtain a mixed layer; fixing the mixed layer in the center of the outer layer mold, uniformly coating outer layer slurry in the gap position, pressurizing with 17N pressure to drive the residual air, standing for more than 5 minutes to cure to obtain the preparation, and storing at 5 ℃ for later use.
In particular, all embodiments of the present invention have excellent therapeutic effects on bone tuberculosis.
In order to verify the effect of the streptomycin calcium sulfate sustained-release preparation prepared according to the creation point of the invention, the following verification experiment is carried out:
1. experimental Material
Streptomycin sulfate for injection (Shandong Lu anti-medicine, Inc., 1 g/bottle in specification); calcium sulfate for medical use (british baisai, 5CC si di bone powder); shimadzu model LC-15C high performance liquid chromatograph (Shimadzu, Japan); neoferrite 18R high speed refrigerated centrifuge (likang development ltd); JXFSPRP-24 full-automatic sample rapid grinding instrument (Shanghai Jingxin industry development Co., Ltd.); methanol (national chemical group chemical Co., Ltd.), acetonitrile (national chemical group chemical Co., Ltd.), and sodium 1-heptanesulfonate (national chemical group chemical Co., Ltd.)
1.2 preparation of streptomycin calcium sulfate sustained release preparation with different specifications
9 different streptomycin calcium sulfate sustained release granules were prepared by the methods of examples 1 to 9. The prepared granules are sterilized again for half an hour by ultraviolet rays for standby.
1.3 Experimental animals and groups
132 New Zealand white rabbits (6 months old, female and male are not restricted) with the weight of about 2.5kg are selected as experimental animals (provided by animal experiment center of Fujian medical university). Randomly divided into 11 groups, experimental group streptomycin-calcium sulfate particles (A)1Group A2Group A3Group A4Group A5Group A6Group A7Group A8Group A9Groups, corresponding to the granules prepared in examples 1-9, respectively, control group streptomycin (group B), blank group (group C), each group containing 12 individuals.
1.4 Rabbit model establishment
Rabbits were placed in a fixed frame for the experiment and anesthetized by otic intravenous injection using 3% sodium pentobarbital (30 mg/Kg). After the rabbits were completely anesthetized, the supine position was fixed on the operating table. Skin preparation is carried out on the operation area of the upper section of the tibia of the lower limb at one side, and a towel is laid after disinfection by alcohol and iodophor. The longitudinal incision is made by taking the inner side of the upper tibial section as the center, and the length is about 3 cm. The skin and subcutaneous tissues were sequentially incised, and the periosteum was peeled off from the muscular space to the inner side of the tibia. Using the position of the upper end of the tibia close to a tibial plateau as a center, slotting by using an electric drill, gradually expanding the hole to a cylindrical bone defect with the diameter of 10mm and the depth of 6mm, flushing the wound by using normal saline, and preparing A1-A9Group granules were implanted in bone defects, group B was streptomycin and group C was left untreated. A. the1-A94 particles of sterilized granules are placed in the group holes, and the group B is implanted and the group A3The same weight of streptomycin was added to the group. The fascia is sutured to wrap the skeletal wound surface, and the fascia and the skin are sutured in sequence. And (5) putting the fish back into a cage for breeding and observing. 250mg of cefazolin sodium is injected into the experiment intramuscular for 3 days continuously.
1.5 Observation index
1.5.1 blood concentration measurement
Taking 3A at 8w after operation1-A9After the experimental rabbits of the group are anesthetized by the auricular edge vein of sodium pentobarbital (1mg/Kg), 1ml of blood of the contralateral auricular edge vein is taken for detection; weighing 4 pieces of tissue with size of 0.5mg at a hole radius of 5mm, respectively pulverizing, adding 5ml PBS, homogenizing, centrifuging at 400r/min for 15min, and collecting supernatant, and freezing at-20 deg.C. And (3) measuring the streptomycin concentration by using high performance liquid chromatography.
3 Ax groups (A) are taken respectively at 1d, 2d, 3d, 1w, 2w, 4w, 6w, 8w and 10w after operation1-A9In the group with the best slow release effect), the experimental rabbits of the group B and the group C are anesthetized by the auricular edge vein of pentobarbital sodium (1mg/Kg), and 1ml of blood of the opposite auricular edge vein is taken for detection; weighing 4 pieces of tissue with size of 0.5mg at hole radius of 5mm, pulverizing respectively, and adding 5ml PBSHomogenizing, centrifuging at 400r/min for 15min, and freezing and storing the supernatant at-20 deg.C. And (3) measuring the streptomycin concentration by using high performance liquid chromatography.
1.5.2 determination of tissue compatibility of streptomycin calcium sulfate sustained-release System
According to the group Ax of the embodiment group with the best detection effect of the blood concentration after operation, 2w and 6w tissues of the implantation part, liver and kidney of the experimental rabbit after operation are taken and conventionally prepared into pathological sections, HE staining and optical microscope observation are carried out.
Taking blood from 2w and 6w experimental rabbits after operation, and performing conventional liver and kidney function tests.
1.5.3 streptomycin calcium sulfate sustained release system osteogenesis detection
(1) Ax group (A)1-A9The group with the best slow release effect) experimental rabbits carry out X-ray examination on implanted parts at 1w, 2w, 4w and 8w lines after operation to know the osteogenesis condition;
(2) ax group of 8w postoperatively (A)1-A9Group with best slow release effect) the implantation part of the experimental rabbit is taken, pathological sections are made, and the condition of osteogenesis is examined by a light mirror.
2. Results of the experiment
2.1 drug metabolism data are shown in Table 1
Table 1: a. the1group-A9Blood concentration data of group and control group
| Time | A1 | A2 | A3 | A4 | A5 | A6 | A7 | A8 | | Control group | |
| 1d | 0.51 | 0.52 | 0.54 | 0.51 | 0.55 | 0.56 | 0.36 | 0.39 | 0.33 | 17.49 | |
| 2d | 1.55 | 1.62 | 1.62 | 1.57 | 1.58 | 1.57 | 1.08 | 0.90 | 0.73 | 78.76 | |
| 3d | 3.16 | 3.38 | 3.14 | 3.19 | 3.20 | 3.14 | 2.10 | 2.19 | 1.34 | 159.32 | |
| 1w | 12.17 | 12.90 | 16.05 | 12.20 | 12.21 | 11.97 | 10.73 | 9.89 | 4.96 | 27.58 | |
| 2w | 52.15 | 55.72 | 40.07 | 52.18 | 52.19 | 51.01 | 26.79 | 32.90 | 19.43 | 0.05 | |
| 3w | 51.08 | 55.81 | 44.38 | 51.10 | 51.11 | 49.55 | 29.67 | 36.45 | 31.01 | 0.00 | |
| 4w | 34.49 | 37.19 | 42.45 | 34.51 | 34.52 | 33.63 | 28.38 | 34.86 | 25.39 | ||
| 5w | 17.91 | 20.04 | 20.51 | 17.94 | 17.95 | 17.25 | 13.71 | 16.82 | 12.23 | ||
| 6w | 12.44 | 12.77 | 8.73 | 12.47 | 12.47 | 12.38 | 5.84 | 7.13 | 4.70 | ||
| 7w | 6.32 | 6.59 | 4.34 | 6.35 | 6.36 | 6.28 | 2.90 | 3.52 | 2.45 | ||
| 8w | 2.19 | 2.43 | 1.68 | 2.21 | 2.22 | 2.15 | 1.12 | 1.33 | 0.94 | ||
| 9w | 0.05 | 0.05 | 0.09 | 0.07 | 0.08 | 0.09 | 0.06 | 0.02 | 0.16 | ||
| 10w | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 |
As can be seen from the above table, A1-A9The blood concentration of the group was enriched at 2w-3w, and decreased rapidly and slowly at 4w and thereafter, while the control group began to enrich at 3d and streptomycin content was not detected after 1 w. Thus, invention A1 -A9Compared with a control group, the sustained-release effect is better, and after 9w, the sustained release is ended, while the streptomycin treatment on the bone tuberculosis is locally continued for 8w of effective bactericidal concentration.
A7-A8The layered slow release of the components has no obvious difference on the slow release effect relative to the A1-A6 groups, and the slow release trend is the same, therefore,the layered slow release increases the slow release of nutrient substances and promotes the effect of bone repair on the premise of not influencing the slow release effect; the layered slow release system has the beneficial effects that the increased nutrient substances slow down the slow release speed, the nutrient substances and the calcium sulfate are considered to have wrapping or interaction, and in the process of streptomycin release, hydrophilic and hydrophobic molecular clathrates formed by the calcium sulfate and the nutrient substances form a new balance of the slow release system.
TABLE 2A3Group blood drug concentration and tissue drug concentration data
Example 3 group of plasma concentration curves, as shown in fig. 1, tissue metabolic concentration curves, as shown in fig. 2;
the control group blood concentration curve is shown in fig. 3, and the control group blood concentration curve is shown in fig. 4.
2.2 determination of histocompatibility of the streptomycin calcium sulfate sustained-release system, as shown in FIGS. 5 to 8.
The following experimental groups refer to example 3.
At 2 weeks in the experimental group, the rat liver is sliced, and HE staining shows that no obvious abnormality is seen in macrophages and hepatocytes. The liver blood sinuses, liver plate and lobular veins are not abnormal. The experimental group has the kidney section HE staining, and the comparison with the control group at 6 weeks shows that the renal cortex, the renal tubules, the proximal tubules and the distal tubules are not abnormal, and the control group has no abnormality.
As shown in FIGS. 5 to 8, at 2 weeks in the experimental group, the rat liver was sectioned and HE-stained, indicating that no obvious abnormality was observed in macrophages and hepatocytes. The liver blood sinuses, liver plate and lobular veins are not abnormal. The experimental group has the kidney section HE staining, and the comparison with the control group at 6 weeks shows that the renal cortex, the renal tubules, the proximal tubules and the distal tubules are not abnormal, and the control group has no abnormality.
FIG. 5 shows that HE staining of experimental group at 2 weeks after surgery shows that there is no abnormality in glomeruli and tubules (HE X40); FIG. 6 shows that there was no abnormality in glomeruli and renal tubules for 6 weeks after the operation, and no drug damage (HE X40); FIG. 7 shows that in the rabbit liver tissue hepatic portal zone after 2 weeks of operation, macrophage and hepatocyte morphologies are normal; (HE × 40); FIG. 8 shows that there is no abnormality in macrophages and hepatocytes (HE X40) in the hepatic portal zone of the liver tissue of rabbits at 6 weeks after the operation;
2.3 examination of blood, liver, kidney and function
The examination of liver function and kidney function shows that the animal has no obvious increase of alanine aminotransferase ALT, aspartate aminotransferase AST, creatinine CR and urea nitrogen BUN after 2 weeks compared with the normal control group, and the difference has no statistical significance (P > 0.05).
The examination of liver function and kidney function shows that the animal has alanine aminotransferase ALT, aspartate aminotransferase AST, creatinine CR and urea nitrogen BUN after 6 weeks, and has no obvious increase compared with the normal control group, and the difference has no statistical significance (P > 0.05).
The indexes of alanine aminotransferase ALT, aspartate aminotransferase AST, creatinine CR and urea nitrogen BUN are not obviously increased in the preoperative and postoperative experimental groups, and the difference has no statistical significance (P > 0.05).
TABLE 3 comparison of the results of the liver function and renal function blood-drawing tests at 2 weeks of the operation
TABLE 4 comparison of liver function and renal function blood-drawing test results at 6 weeks of surgery
The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all modifications of equivalent structures and equivalent processes performed by the present specification and drawings, or directly or indirectly applied to other related technical fields, are included in the scope of the present invention.
Claims (6)
1. A streptomycin calcium sulfate sustained release preparation is characterized in that: the preparation comprises the following components, by weight, 0.5-9 parts of streptomycin sulfate, 2.6-21 parts of calcium sulfate and 1-9 parts of water for sterilization and injection, wherein the preparation is particles, the diameter of the particles is not more than 4mm, the particles are sequentially and tightly connected into an inner release layer, a middle release layer and an outer release layer from inside to outside, and the particles are in a cylindrical structure, a spherical structure or a spiral structure;
the inner release layer mainly comprises glycosaminoglycan, calcium sulfate, streptomycin sulfate and sterilized water for injection;
the middle release layer mainly comprises bone peptide, calcium sulfate, streptomycin sulfate and sterilized water for injection;
the outer release layer mainly comprises calcium sulfate, streptomycin sulfate and sterilized water for injection.
2. The streptomycin calcium sulfate sustained release formulation of claim 1, wherein: the sterilization injection comprises, by weight, 0.5-3 parts of streptomycin sulfate, 2.6-7 parts of calcium sulfate and 1-3 parts of sterilization injection water.
3. The streptomycin calcium sulfate sustained release formulation of claim 1, wherein: also comprises 2.6-5 parts of glycosaminoglycan and 2.6-5 parts of bone peptide.
4. The streptomycin calcium sulfate sustained release formulation of claim 1, wherein: the inner release layer mainly comprises the following components, by weight, 2.6-5 parts of glycosaminoglycan, 2.6-7 parts of calcium sulfate, 0.5-3 parts of streptomycin sulfate and 1-3 parts of sterilized water for injection; the middle release layer mainly comprises the following components, by weight, 2.6-5 parts of bone peptide, 2.6-7 parts of calcium sulfate, 0.5-3 parts of streptomycin sulfate and 1-3 parts of sterilized water for injection; the outer release layer mainly comprises the following components, by weight, 0.5-3 parts of streptomycin sulfate, 2.6-7 parts of calcium sulfate and 1-3 parts of sterilized water for injection.
5. A method for preparing a streptomycin calcium sulfate sustained release preparation according to claim 1, which is characterized in that: comprises the following steps of (a) carrying out,
s1, placing streptomycin sulfate powder and calcium sulfate powder in corresponding weight parts in a sterile environment, and uniformly stirring;
s2, adding corresponding parts by weight of sterilized water for injection, fully stirring for 20-40 seconds at low temperature until the paste is uniform and pasty, dividing into three parts, wherein one part is used as external release slurry for later use, the other part is added with corresponding parts by weight of glycosaminoglycan to obtain inner layer slurry for later use, and the other part is added with corresponding parts by weight of bone peptide to obtain middle layer slurry for later use;
s3, uniformly coating inner release layer slurry on an inner release layer mould with a corresponding shape, pressurizing with the pressure of 15-20N to drive the residual air, standing for 10-15 minutes to cure to obtain an inner release layer;
s4, fixing the inner release layer in the center of the middle release layer mold, uniformly coating middle layer slurry at the position of the gap, pressurizing by using the pressure of 15-20N to drive the residual air, standing for 10-15 minutes and curing to obtain a mixed layer;
s5, fixing the mixed layer in the center of an outer layer die, uniformly coating outer layer slurry at the position of a gap, pressurizing by using the pressure of 15-20N to drive the residual air, standing for more than 10 minutes to solidify to obtain a preparation, and storing at low temperature for later use;
the low-temperature stirring and mixing temperature is 0-5 ℃, and the standing time in the mold is 2-4 ℃ of the low-temperature storage temperature.
6. Use of a streptomycin calcium sulfate sustained release formulation according to any one of claims 1 to 3 for the manufacture of a medicament for placement in bone marrow for surgical treatment of bone tuberculosis.
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