CN103143024B - Implantable kidney-tonifying bone-invigorating traditional Chinese medicine extract-antibiotic-calcium sulfate sustained-release system, and preparation method and application thereof - Google Patents

Abstract

The invention belongs to the technical field of implantable sustained-release drug delivery systems, and in particular relates to a Chinese medicine extract-antibiotic-calcium sulfate sustained-release system for nourishing the kidney and strengthening bones and its preparation method and application. The slow-release system includes the following components in terms of mass: 0.1-1.0 parts of kidney-tonifying and bone-strengthening traditional Chinese medicine extract, 0.1-2.0 parts of antibiotics, and 5-20 parts of calcium sulfate carrier. It has synergistic and detoxifying effects of traditional Chinese and Western medicine, effectively promotes the healing of bone infection, reduces complications, and improves the cure rate.

Description

An implantable extract-antibiotic-calcium sulfate slow-release system of traditional Chinese medicine for invigorating the kidney and strengthening the bones, its preparation method and application

technical field

The invention belongs to the technical field of implantable sustained-release drug delivery systems, and in particular relates to a Chinese medicine extract-antibiotic-calcium sulfate sustained-release system for nourishing the kidney and strengthening bones and its preparation method and application.

Background technique

The incidence of osteomyelitis and other bone defects combined with bone infection is on the rise due to social development, and the treatment is difficult. It is a difficult disease that needs to be solved urgently in the field of surgery. Clinical treatment is based on surgical removal of sequestrum and fibrotic tissue, followed by tissue flap transplantation or bone transplantation, and antibiotic treatment. Because it is difficult for intravenous or oral antibiotics to enter the deep part of the infection to kill bacteria, and the course of the disease is long, long-term use of antibiotics is required, which will inevitably increase the amount of antibiotics and treatment costs, and easily cause adverse drug reactions. Therefore, the use of antibiotic-loaded implant materials for local sustained-release administration can not only exert local anti-infection effects, but also have sustained-release effects, and have fewer systemic side effects. It is currently a commonly used clinical treatment. The early material bone cement (polymethyl methacrylate, PMMA) was once favored, but it was gradually replaced by other materials due to the need for secondary surgery: such as polylactic acid and polyglycolic acid, polycaprolactone, hydroxyl Apatite and coral hydroxyapatite complexes, collagen gelatin, recombinant heterogeneous bone complexes, chitosan and its derivatives, liposomes, nanomaterials, bioactive glass-ceramic and other absorbable and sustained-release materials instead, among which Calcium sulfate artificial bone sustained-release system is widely used. This carrier can be used by new bone formation, has good biocompatibility and osteoconductivity, as well as low antibiotic dosage and short drug cycle. It has become the current osteomyelitis treatment. main implant carrier. The space pattern of the columnar crystals of the carrier and the antibiotic form a good network drug storage shape, and after implantation in the body, the drug contained in it is released with the degradation and erosion of the carrier, exerting a slow-release effect, and continuously maintaining a high local antibiotic drug concentration. Commonly used clinical antibiotics such as vancomycin, tobramycin and gentamicin are suitable for this carrier, such as the Chinese invention patent application (application number: 200510131093.2 application date: 2005-12-07) and the Chinese invention patent application (application No.: 03148624.X Application date: 2003-06-23). Clinical application has proved to have a good antibacterial effect, but the effect on bone healing is not obvious, and high concentrations of antibiotics may have an inhibitory effect on bone healing, so the incidence of delayed bone healing (bone nonunion) in clinical treatment is relatively high.

Modern studies have proved that a variety of traditional Chinese medicines for invigorating the kidney and strengthening bones can promote the proliferation of osteoblasts. For example, icariin, psoralen and rhizoma drynaria can regulate OPG/RANK/RANKL and TGF-β/BMPs signaling pathways, induce bone differentiation and growth, promote bone growth and healing, and exert its osteogenic effect. It has been proved that it can improve local blood circulation, and correct the excess and decline of yin and yang of viscera, qi, blood, and yin and yang through the regulation of the meridian system, tonify deficiency and relieve excess, and improve the general condition. Therefore, the effective components of traditional Chinese medicines that have the function of nourishing the kidney and strengthening the bones are extracts of Chinese medicines for nourishing the kidney and strengthening the bones. At present, there is no calcium sulfate sustained-release preparation combined with traditional Chinese medicine ingredients and antibiotics for experimental research and clinical treatment of osteomyelitis.

Contents of the invention

In order to solve the technical defects of the antibiotic-carrier drug delivery system, the first object of the present invention is to provide an implantable kidney-tonifying and bone-strengthening traditional Chinese medicine extract-antibiotic-calcium sulfate slow-release system, which may promote bone growth while inhibiting bacteria. Quality healing, play synergistic and detoxifying effect, help to shorten the bone healing time, reduce the incidence of nonunion, and improve the comprehensive curative effect. The second object of the present invention is to provide a preparation method of the above-mentioned sustained-release system. The third object of the present invention is to provide the application of the above-mentioned slow-release system.

In order to achieve the above-mentioned first purpose, the present invention adopts the following technical solutions:

An implantable kidney-tonifying and bone-strengthening Chinese medicine extract-antibiotic-calcium sulfate slow-release system, the slow-release system includes the following components by mass fraction:

0.1-1.0 parts of traditional Chinese medicine extract for invigorating kidney and strengthening bones,

Antibiotics 0.1-2.0 copies,

Calcium sulfate carrier 5-20 parts,

Preferably, the slow-release system includes the following components by mass fraction:

0.1-0.3 copies of traditional Chinese medicine extract for invigorating the kidney and strengthening the bones,

Antibiotics 0.3-1.2 parts,

Calcium sulfate carrier 8-10 parts,

Water for injection 0-4 parts.

Preferably, the slow-release system further includes 0-2 parts of polylactic acid and 0-2 parts of sodium alginate in terms of mass fractions.

Preferably, the Chinese medicine extract for invigorating the kidney and bone is selected from one or more of the total glycosides of icarii, the total flavonoids of drynariae, the total flavonoids of psoraleae, the total saponins of Achyranthes bidentata, the total flavonoids of Cuscuta chinensis and the total flavonoids of mistletoe Various mixes.

Preferably, the antibiotic is selected from one or more mixtures of Pioneer IV, vancomycin, gentamicin, tobramycin, teicoplanin, cephalosporins and quinolones.

Preferably, the slow-release system is composed of the following components in terms of mass fractions: 0.1-0.3 parts of total icariin, 0.5-1.2 parts of vancomycin hydrochloride powder injection, 8-10 parts of calcium sulfate, and 2-2 parts of water for injection. 4 parts.

Preferably, the slow-release system is composed of the following components in terms of mass fractions: 0.1-0.3 parts of icariin, 0.10-0.50 parts of tobramycin sulfate injection, 0.2-1.0 parts of sodium alginate, calcium sulfate 8~10 servings.

In order to achieve the above-mentioned second purpose, the present invention adopts the following technical solutions:

A method for preparing the implantable kidney-tonifying and bone-strengthening traditional Chinese medicine extract-antibiotic-calcium sulfate slow-release system described in any one of the above technical solutions, the method comprises the following steps:

1) According to the prescription ratio, weigh the calcium sulfate carrier, put it in a clean container, and set aside;

2) According to the proportion of the prescription, weigh the Chinese medicine extract for invigorating the kidney and strengthening the bones, and set aside;

3) Weigh the antibiotic according to the proportion of the prescription. If the antibiotic is a liquid preparation, convert the required volume according to the marked amount of the injection, draw the antibiotic according to the proportion, add it to the Chinese medicine extract for nourishing kidney and strengthening bones in step 2), and mix well to form a mixture Or dissolve into a clear solution for later use;

4) If the antibiotic is a solid preparation, draw sterilized physiological saline, add it to the mixture in step 3), dissolve into a clear solution, and set aside;

5) Take the clear solution in step 4), add it to the carrier material in step 1), stir quickly and evenly, transfer it to the corresponding mold immediately with a spatula, fill it up and remove air bubbles, leave it for 5-10 minutes, and take it out after it is completely cured; That is tonify the kidney and strengthen the bone Chinese medicine extract-antibiotic-calcium sulfate sustained-release preparation;

If the antibiotic is a liquid preparation, directly take the clear solution in step 3), add it to the carrier material in step 1), stir quickly and evenly, transfer it to the corresponding mold with a spatula immediately, fill it up and remove air bubbles, and place it for 5-10min and take it out after being completely cured; the Chinese medicine extract-antibiotic-calcium sulfate sustained-release preparation for invigorating the kidney and strengthening the bones is obtained.

In order to achieve the above-mentioned third purpose, the present invention adopts the following technical solutions:

The implantable kidney-reinforcing and bone-strengthening traditional Chinese medicine extract-antibiotic-calcium sulfate slow-release system described in any one of the above technical solutions is used in the preparation of medicines for treating orthopedic bone infection or bone defect.

Preferably, the implantable kidney-tonifying and bone-strengthening traditional Chinese medicine extract-antibiotic-calcium sulfate slow-release system described in any one of the above technical solutions is used in the preparation of medicines for treating chronic osteomyelitis.

The present invention has the following advantages due to the adoption of the above-mentioned technical scheme:

1. Using the combination of traditional Chinese medicine and antibiotics to prepare implantable preparations with sustained release effect, the drug effect lasts for more than 1 month, exert the synergistic effect of antibiotic antibacterial and traditional Chinese medicine to promote bone growth, and continuously exert antibiotic antibacterial anti-infection, Traditional Chinese medicine promotes bone growth and healing, and the drug effect lasts for a long time. It has the synergistic and attenuating effect of integrated Chinese and Western medicine, effectively promotes the healing of bone infection, reduces complications, and improves the cure rate; and the sustained release system can be combined with other drugs , preparing an implantable sustained-release drug preparation;

2. Using calcium sulfate as a carrier, systematically study the compatibility of antibiotics and bone-promoting components of various traditional Chinese medicines, prepare implantable sustained-release drug preparations, and use advanced technologies such as scanning electron microscopy and instrumental analysis to analyze the spatial structure of the preparations-erosion- Drug release-time rule, preparation of sustained-release preparations that meet clinical needs, provide experimental basis for further clinical application, and the invention content has good application prospects.

Description of drawings

Fig. 1 is an in vitro simulated drug release-time curve of the icariin-vancomycin-calcium sulfate sustained-release system provided by the embodiment of the present invention.

Figure 2 is a comparison chart of the therapeutic effect of the epimedium total glucosides-vancomycin-calcium sulfate sustained-release system provided by the embodiment of the present invention on chronic osteomyelitis rabbits.

Detailed ways

In order to make the object, technical solution and advantages of the present invention clearer, the present invention will be further described in detail below in conjunction with the accompanying drawings and embodiments.

The embodiment of the present invention provides an implantable Chinese medicine extract-antibiotic-calcium sulfate slow-release system for invigorating the kidney and strengthening the bones. The basic formula of the slow-release system is prepared by the following auxiliary materials in parts by weight:

0.1-1 part of traditional Chinese medicine extract for invigorating kidney and strengthening bones, 0.1-2 parts of antibiotics, 0-2 parts of polylactic acid, 0-2 parts of sodium alginate, 5-10 parts of calcium sulfate carrier, and 0-5 parts of water for injection.

 This system is composed of the basic formula of the above-mentioned drug delivery system. The ingredients involved in the kidney-tonifying and bone-reinforcing traditional Chinese medicine extract and antibiotics are as follows:

Bone-promoting ingredients of traditional Chinese medicine: total icariin, or total flavonoids of drynariae, or total flavonoids of psoralen, or total saponins of Achyranthes bidentata, or total flavonoids of Cuscuta, or total flavonoids of mistletoe; antibiotics: including pioneer IV, vancomycin Factors such as gentamicin, tobramycin, teicoplanin, cephalosporins and quinolones.

The present invention has also determined that the optimum formula of icariin-antibiotic-calcium sulfate slow-release system is:

Epimedium glycosides 0.12g, vancomycin hydrochloride powder injection 0.9g, calcium sulfate 9.5g, water for injection 3ml;

Epimedium glycosides 0.12g, Tobramycin Sulfate Injection 0.12g (3ml), Sodium Alginate 0.6g, Calcium Sulfate 9.5g.

Example 1

The operation steps of the preparation method of icariin-vancomycin-calcium sulfate sustained-release preparation are as follows:

1) According to the proportion of the prescription, weigh 9.5g of calcium sulfate carrier, put it in a clean container, and set aside;

2) According to the proportion of the prescription, weigh 0.12g of total icariin (the content of icariin is >10% after content determination) and set aside;

3) According to the prescription ratio, weigh 0.88g of vancomycin hydrochloride powder injection, add it to the total icariin in step 2), mix well to form a mixture, and set aside;

4) Draw 3ml of sterilized physiological saline, add it to the mixture in step 3), dissolve into a clear solution, and set aside;

5) Take the solution in step 4), add it to the carrier material in step 1), stir quickly and evenly, and immediately transfer it to the corresponding mold with a spatula, fill it up and remove air bubbles, place it for 5-10 minutes, and take it out after it is completely cured; Obtained icariin-vancomycin-calcium sulfate sustained-release preparation; measured content, total icariin content was 9.2mg/g (wherein icariin 1.0mg/g), vancomycin content was 66.7 mg/g.

Example 2

The operation steps of the preparation method of icariin-tobramycin-calcium sulfate sustained-release preparation are as follows:

1) According to the proportion of the prescription, weigh 9.5g of calcium sulfate carrier, put it in a clean container, and set aside;

2) According to the proportion of the prescription, weigh 0.12g of total icariin (the content of icariin is >10% after content determination), 0.6g of sodium alginate, mix well, and set aside;

3) Take 3ml of tobramycin sulfate, add it to the mixture of icariin and sodium alginate in step 2), dissolve, and if necessary, conduct ultrasound to promote dissolution into a clear solution, and set aside;

4) Take the solution in step 3), add it to the carrier material in step 1), stir quickly and evenly, and immediately transfer it to the corresponding mold with a spatula, fill it up and remove air bubbles, place it for 5-10 minutes, and take it out after it is completely cured; Obtained icariin-tobramycin-calcium sulfate sustained-release preparation; measured content, total icariin content is 9.8mg/g (wherein icariin 1.0mg/g), tobramycin content is 9.8 mg/g.

Example 3

The preparation of Example 1 is used for local implant administration of chronic osteomyelitis rabbit model, and the steps include:

1) According to the proportion of the prescription, weigh 9.5g of calcium sulfate carrier, put it in a clean container, and set aside;

2) According to the proportion of the prescription, weigh 0.12g of total icariin (the content of icariin is >35% after content determination) and set aside;

3) According to the prescription ratio, weigh 0.88g of vancomycin hydrochloride powder injection, add it to the total icariin in step 2), mix well to form a mixture, and set aside;

4) Draw 3ml of sterilized physiological saline, add it to the mixture in step 3), dissolve the clear solution, and set aside;

5) Take the solution in step 4), add it to the carrier material in step 1), stir quickly and evenly, and immediately transfer it to the corresponding mold with a spatula, fill it up and remove air bubbles, place it for 5-10 minutes, and take it out after it is completely cured; Obtain Epimedium glucosides-vancomycin-calcium sulfate sustained-release preparation;

6) Take the sustained-release preparation in step 5), conduct spatial microstructure analysis, and determine the content of antibiotics and index components of traditional Chinese medicines. The measurement results: the content of icariin is 4.2 mg/g, and the content of vancomycin is 86.3 mg/g ;

7) Take a male New Zealand rabbit with a weight of 2-2.5Kg, anesthetize it, make a hole in the tibia (hole diameter 0.3cm), and inoculate Staphylococcus aureus to make a model. After 2 weeks, X-ray examination combined with blood bacterial culture confirms the formation of osteomyelitis rabbits Model;

8) Take the rabbit model in step 7), anesthetize again, and thoroughly debride the wound;

9) Take 3 g of the icariin-vancomycin-calcium sulfate preparation in step 5), and place it evenly in the wound cavity of the osteomyelitis model rabbit in step 8), complete the operation, and embed a drainage tube in the wound to become a treatment model Rabbits; at the same time, a model control group was set up for curative effect comparison;

10) Postoperative observation, lesion X imaging detection, local drug concentration detection, evaluation of curative effect according to the bone growth of the lesion and wound healing;

11) The X-ray examination of the lesion was carried out regularly within 2-10 weeks after the operation. Compared with the model control group, the healing time of the lesion in the treatment model in step 9) was shortened, and the activities of serum osteocalcin and serum alkaline phosphatase were increased (See Figure 2).

Claims (8)

1. embedded type reinforcing the kidney to strengthen the bone Chinese medicine extract-antibiotic-calcium sulfate slow-released system, is characterized in that this slow-released system comprises following component by mass parts:

Reinforcing the kidney to strengthen the bone Chinese medicine extract 0.1-1.0 part,

Antibiotic 0.1-2.0 part,

Calcium sulfate carrier 5-20 part,

Water for injection 0-10 part;

Described reinforcing the kidney to strengthen the bone Chinese medicine extract is selected from general icariin, Process of Total Flavonoids in Drynaria Fortunei, Fructus Psoraleae total flavones, Radix Achyranthis Bidentatae total saponins, one or more mixing in Semen Cuscutae total flavones and Herba Visci total flavones;

Described antibiotic is selected from one or more mixing in pioneer's IV, vancomycin, gentamycin, tobramycin, teicoplanin, cephalo-type and quinolones.

2. a kind of embedded type reinforcing the kidney to strengthen the bone Chinese medicine extract-antibiotic-calcium sulfate slow-released system according to claim 1, is characterized in that this slow-released system comprises following component by mass parts:

Reinforcing the kidney to strengthen the bone Chinese medicine extract 0.1-0.3 part,

Antibiotic 0.3-1.2 part,

Calcium sulfate carrier 8-10 part,

Water for injection 0-4 part.

3. a kind of embedded type reinforcing the kidney to strengthen the bone Chinese medicine extract-antibiotic-calcium sulfate slow-released system according to claim 1 and 2, is characterized in that: this slow-released system also comprises polylactic acid 0-2 part by mass parts sodium alginate 0-2 part.

4. a kind of embedded type reinforcing the kidney to strengthen the bone Chinese medicine extract-antibiotic-calcium sulfate slow-released system according to claim 1, it is characterized in that this slow-released system is made up of following component by mass parts: 0.1 ~ 0.3 part of general icariin, 0.5 ~ 1.2 part of Lyphocin (Fujisawa) injectable powder, 8 ~ 10 parts, calcium sulfate, 2 ~ 4 parts of waters for injection.

5. a kind of embedded type reinforcing the kidney to strengthen the bone Chinese medicine extract-antibiotic-calcium sulfate slow-released system according to claim 1, it is characterized in that this slow-released system is made up of following component by mass parts: 0.1 ~ 0.3 part of general icariin, 0.10 ~ 0.50 part of tobramycin sulfate injection, 0.2 ~ 1.0 part of sodium alginate, 8 ~ 10 parts, calcium sulfate.

6. a method of preparing the embedded type reinforcing the kidney to strengthen the bone Chinese medicine extract-antibiotic-calcium sulfate slow-released system described in claim 1 or 2 or 4 or 5, is characterized in that the method comprises the following steps:

1) in prescription ratio, take calcium sulfate carrier, be placed in clean container, for subsequent use;

2) in prescription ratio, take reinforcing the kidney to strengthen the bone Chinese medicine extract, for subsequent use;

3) in prescription ratio, take antibiotic, if antibiotic is liquid preparation, convert according to injection labelled amount volume required, draw in proportion antibiotic, join step 2) reinforcing the kidney to strengthen the bone Chinese medicine extract in, mix homogeneously resulting mixture or be dissolved into clear and bright solution, for subsequent use;

4) if antibiotic is solid preparation, draw water for injection, join in the mixture of step 3), be dissolved into clear and bright solution, for subsequent use;

5) get the clear and bright solution of step 4), join in the carrier material of step 1), rapid stirring is even, is transferred in corresponding mould immediately with curet, tamps bubble removing side by side, places 5-10min, after solidifying completely, takes out; Obtain reinforcing the kidney to strengthen the bone Chinese medicine extract-antibiotic-calcium sulfate slow releasing preparation;

If antibiotic is liquid preparation, directly get the clear and bright solution of step 3), join in the carrier material of step 1), rapid stirring is even, is transferred in corresponding mould immediately with curet, tamps bubble removing side by side, places 5-10min, after solidifying completely, takes out; Obtain reinforcing the kidney to strengthen the bone Chinese medicine extract-antibiotic-calcium sulfate slow releasing preparation.

7. in the medicine of the embedded type reinforcing the kidney to strengthen the bone Chinese medicine extract-antibiotic-calcium sulfate slow-released system described in claim 1 ~ 5 any one claim for the preparation for the treatment of orthopaedics infection of bone or the damaged disease of bone, apply.

8. in the medicine of the embedded type reinforcing the kidney to strengthen the bone Chinese medicine extract-antibiotic-calcium sulfate slow-released system described in claim 1 ~ 5 any one claim for the preparation for the treatment of chronic osteomyelitis, apply.

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