Bone rehabilitation promoting pills based on traditional Chinese medicine extracts and preparation method thereof

Abstract

The present invention relates to the field of Chinese medicine preparations, and discloses a bone rehabilitation promoting pill based on Chinese medicine extracts and a preparation method thereof, wherein the components of the bone rehabilitation promoting pills include: a Chinese medicine extract, wherein the Chinese medicine extract is one or more of Rhizoma Drynariae, Eucommia ulmoides, Rhizoma Chuanxiong, and Radix Angelicae Sinensis, and the content thereof is 40% to 60% of the total weight of the bone rehabilitation promoting pills; a drug carrier, wherein the drug carrier is polylactic acid, polylactic-co-glycolic acid copolymer, or a complex thereof with nano-calcium phosphate, and the content thereof is 20% to 30% of the total weight of the bone rehabilitation promoting pills; and a cosolvent, wherein the cosolvent is cyclodextrin or phospholipids. By combining Chinese medicine extracts such as Rhizoma Drynariae, Eucommia ulmoides, Rhizoma Chuanxiong, and Radix Angelicae Sinensis with drug carriers such as polylactic acid and polylactic-co-glycolic acid copolymer, the effect of continuous release of drugs and targeting bone tissue when treating diseases such as bone injury and osteoporosis is achieved, and the solution solves the problem of excessively fast release of drugs in vivo, and ensures a long-term effective concentration of drugs in bone tissue.

Description

Technical Field

[0001] The invention relates to the technical field of traditional Chinese medicine preparations, in particular to bone rehabilitation promoting pills based on traditional Chinese medicine extracts and a preparation method thereof. Background Art

[0002] The incidence of bone-related diseases such as bone injuries, fractures, and osteoporosis is increasing year by year worldwide, especially in the elderly population, where the incidence of osteoporosis and fractures has increased significantly. The treatment and rehabilitation of bone injuries is a major problem in clinical medicine. Traditional fracture treatment methods include surgical treatment, physical therapy, and drug therapy, among which drug therapy mainly relies on chemical synthetic drugs, non-steroidal anti-inflammatory drugs, and traditional Chinese medicine preparations. Traditional Chinese medicine has a long history in bone rehabilitation treatment. Many traditional Chinese medicines such as Drynaria fortunei, Angelica sinensis, and Eucommia ulmoides are used to promote bone repair, enhance bone density, and improve bone quality. However, existing traditional Chinese medicine preparations often face problems such as unstable efficacy, unsustainable drug release, and poor targeting when treating diseases such as fractures and osteoporosis, which limits their efficacy.

[0003] At present, bone rehabilitation preparations based on Chinese medicine extracts have gradually entered the market, among which common drugs such as bone drynaria, eucommia, angelica, chuanxiong and other extracts are used in the rehabilitation treatment of bone injuries. Most of the existing Chinese medicine preparations for fracture rehabilitation are administered by oral administration, topical application and other methods, and their preparation forms include granules, tablets, capsules and the like. However, these drug preparations still have some disadvantages in the application process. First, the drug release rate is fast, which easily leads to rapid metabolism of the drug in the body, making it difficult to maintain the continuity of the drug effect, especially in the treatment of diseases such as fractures and osteoporosis that require long-term effects. It is difficult to ensure the long-term effective concentration of the drug in the body. Secondly, the traditional drug carrier lacks targeting, resulting in uneven distribution of the drug, making it difficult to effectively accumulate on bone tissue, thereby reducing the therapeutic effect of the drug. Furthermore, the existing Chinese medicine extracts have low solubility and poor bioavailability, which affects their absorption and efficacy in the body. Finally, conventional fillers are mostly used in existing preparations, and the effects of these fillers in terms of stability and release rate control are not satisfactory.

[0004] In the prior art, although a variety of Chinese herbal extracts have been applied to the treatment of bone rehabilitation, the problems of sustained release and targeting of drugs have not been effectively solved. In traditional drug preparations, drugs often enter the body in an uncontrolled release manner, causing the drug efficacy to disappear in a short period of time, making it difficult to maintain the long-term effective concentration of the drug. At the same time, most existing drug carrier materials lack targeting of bone tissue, resulting in uneven distribution of drugs, which cannot concentrate on bone tissue and reduce the effect of fracture healing. Summary of the invention

[0005] In view of the deficiencies in the prior art, the present invention provides bone rehabilitation promoting pills based on Chinese herbal extracts and a preparation method thereof, which solves the problem that in traditional drug preparations, drugs often enter the body in an uncontrolled release manner, causing the drug efficacy to disappear in a short period of time and making it difficult to maintain the drug's effective concentration for a long time.

[0006] To achieve the above objectives, the present invention is implemented by the following technical scheme: bone rehabilitation promoting pills based on Chinese herbal medicine extracts, the components of the bone rehabilitation promoting pills include: Traditional Chinese medicine extract, wherein the traditional Chinese medicine extract is one or more of Drynaria fortunei, Eucommia ulmoides, Ligusticum chuanxiong, and Angelica sinensis, and the content of the traditional Chinese medicine extract is 40% to 60% of the total weight of the bone recovery promoting pill; A drug carrier, wherein the drug carrier is polylactic acid, polylactic acid-glycolic acid copolymer, or a complex thereof with nano-calcium phosphate, and the content of the drug carrier is 20% to 30% of the total weight of the bone rehabilitation promoting pills; A cosolvent, wherein the cosolvent is cyclodextrin or phospholipid; A synergist, which is phospholipids, glycerol or other compatible substances; Filler, the filler is hydroxypropyl methylcellulose and microcrystalline cellulose, and the content of the filler is 5% to 15% of the total weight of the bone rehabilitation promoting pills.

[0007] Preferably, the Chinese medicine extract is a Drynaria extract, which is obtained by solvent extraction, the solvent is water or an alcohol solvent, and the active ingredient in the extract is 20% to 30%.

[0008] Preferably, the drug carrier is polylactic acid and polylactic-co-glycolic acid, and the molecular weight of the copolymer is 30,000 to 100,000.

[0009] Preferably, the drug carrier further comprises nano-calcium phosphate, and the content of the nano-calcium phosphate is 5% to 15% of the total weight of the drug carrier.

[0010] Preferably, the co-solvent is cyclodextrin, and the content of the cyclodextrin is 5% to 7% of the total weight of the bone rehabilitation promoting pills.

[0011] Preferably, the enhancer is phospholipid, and the content of the phospholipid is 5% to 7% of the total weight of the bone rehabilitation promoting pills.

[0012] Preferably, the surface of the drug carrier is modified with phosphate groups or hydroxyl groups so that the drug carrier has bone tissue targeting, and the concentration of the phosphate groups or hydroxyl groups is 0.5% to 5%.

[0013] Preferably, the outer layer of the drug carrier is made of polylactic acid-glycolic acid material, the inner layer is made of polylactic acid material, and the inner layer is 5 to 50 The thickness of the outer film is 2 to 10 .

[0014] The present invention also provides a method for preparing bone rehabilitation promoting pills based on traditional Chinese medicine extracts, comprising the following steps: Step 1, mixing the Chinese herbal medicine extract with a solvent to obtain a Chinese herbal medicine extract solution; Step 2, dissolving polylactic acid and polylactic acid-glycolic acid copolymer in an organic solvent to obtain a solution; Step 3, mixing the Chinese herbal medicine extract solution with the drug carrier solution to obtain a drug carrier-loaded Chinese herbal medicine extract mixture; Step 4, preparing the mixture into particles or microspheres by spray drying or solvent evaporation; Step 5: Mix the particles or microspheres with a solvent and a filler to prepare bone recovery promoting pills.

[0015] Preferably, the solvent is dichloromethane, ethanol or water, and the spray drying temperature is 40 Up to 60 The treatment time of the spray drying or solvent evaporation method is 30 to 120 minutes.

[0016] The present invention provides a bone rehabilitation promoting pill based on a traditional Chinese medicine extract and a preparation method thereof, which has the following beneficial effects: 1. The present invention combines Chinese herbal extracts such as Drynariae Rhizoma, Eucommia ulmoides, Rhizoma Chuanxiong, and Angelicae Sinensis with drug carriers such as polylactic acid and polylactic-co-glycolic acid, thereby achieving the effect of sustained drug release and targeting bone tissue in the treatment of diseases such as bone injury and osteoporosis. Compared with the prior art that simply uses chemically synthesized drugs or Chinese herbal preparations without a controlled release mechanism, this solution solves the problem of too fast drug release in the body and difficulty in maintaining long-term therapeutic effects, and ensures a long-term effective concentration of the drug in bone tissue.

[0017] 2. The present invention adds nano calcium phosphate to the drug carrier and adopts surface modification technology to make the carrier bone tissue targeted, which can more effectively guide the drug to the bone tissue and increase the local concentration. Compared with the prior art that only relies on the intrinsic active substances of the drug or traditional carrier materials, this technical solution solves the shortcomings of poor drug targeting and difficulty in concentrating the drug in bone tissue, enhances the bone tissue repair effect, and improves the accuracy and effect of treatment.

[0018] 3. The present invention uses cyclodextrin or phospholipids as cosolvents, and combines phospholipids, glycerol and other synergists to significantly improve the solubility and bioavailability of Chinese medicine extracts. Compared with the use of Chinese medicine extracts with poor solubility or preparations without synergistic mechanisms in the prior art, the present invention solves the problem of poor absorption of Chinese medicine ingredients in the body, ensures better efficacy, reduces the residence time of the drug in the gastrointestinal tract, and accelerates its speed of reaching the target site through blood circulation.

[0019] 4. The present invention optimizes the dosage form of bone rehabilitation promoting pills by using hydroxypropyl methylcellulose and microcrystalline cellulose as fillers, and improves the physical stability of the preparation and the sustainability of drug release. Compared with other fillers or directly formed pills used in the prior art, this filler combination not only enhances the shape stability of the pills, but also can regulate the slow release of the drug, so that the drug maintains a stable concentration in the patient's body, avoids the problem of too fast release of traditional preparations, and improves the patient's treatment compliance. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 The figure is a flow chart of the method of the present invention. DETAILED DESCRIPTION

[0021] The following will be combined with the drawings in the specification of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0022] Please see attached Figure 1 The embodiment of the present invention provides a bone rehabilitation promoting pill based on a traditional Chinese medicine extract, and the components of the bone rehabilitation promoting pill include: Traditional Chinese medicine extract, the traditional Chinese medicine extract is one or more of Drynaria fortunei, Eucommia ulmoides, Chuanxiong rhizome, and Angelica sinensis, and the content thereof is 40% to 60% of the total weight of the bone recovery promoting pill; Drug carrier, the drug carrier is polylactic acid, polylactic acid-glycolic acid copolymer, or a complex thereof with nano-calcium phosphate, and the content of the drug carrier is 20% to 30% of the total weight of the bone rehabilitation promoting pills; A cosolvent, which is cyclodextrin or phospholipid; Synergist, which is phospholipid, glycerol or other compatible substances; Fillers: fillers are hydroxypropyl methylcellulose and microcrystalline cellulose, and their content is 5% to 15% of the total weight of the bone recovery promoting pills.

[0023] The Chinese medicine extract is Drynaria fortunei extract, which is obtained by solvent extraction, the solvent is water or alcohol solvent, and the active ingredient in the extract is 20% to 30%.

[0024] The drug carrier is polylactic acid and polylactic acid-glycolic acid copolymer, and the molecular weight of the copolymer is 30,000 to 100,000.

[0025] The drug carrier further comprises nano calcium phosphate, and the content of the nano calcium phosphate is 5% to 15% of the total weight of the drug carrier.

[0026] The co-solvent is cyclodextrin, and the content of cyclodextrin is 5% to 7% of the total weight of the bone recovery promoting pills.

[0027] The enhancer is phospholipid, and the content of phospholipid is 5% to 7% of the total weight of the bone recovery promoting pills.

[0028] The surface of the drug carrier is modified with phosphate groups or hydroxyl groups so that the drug carrier has bone tissue targeting, and the concentration of the phosphate groups or hydroxyl groups is 0.5% to 5%.

[0029] The outer layer of the drug carrier is made of polylactic acid-glycolic acid material, and the inner layer is made of polylactic acid material. , the thickness of the outer film is 2 to 10 .

[0030] In this embodiment, the components of bone rehabilitation promoting pills include Chinese medicine extracts, drug carriers, cosolvents, enhancers and fillers. The ratio and selection of the components are carefully designed to ensure that the drug can maintain an effective concentration in the body for a long time, providing a sustained therapeutic effect for diseases such as bone injuries and osteoporosis.

[0031] First, the Chinese medicine extract can be one or more of Drynaria, Eucommia, Chuanxiong, and Angelica. According to an embodiment of the present invention, the content of the Chinese medicine extract is 40% to 60% of the total weight of the bone rehabilitation promoting pill. In some embodiments, the extract of Drynaria is a Drynaria extract extracted by water or alcohol solvents, and its active ingredient content is 20% to 30%. This extract has a strong bone repair effect, can promote the regeneration and repair of bone tissue, and plays an important role in the rehabilitation process after osteoporosis and fracture. As a choice, the present embodiment uses a compound of Drynaria extract and other Chinese medicine extracts such as Eucommia, Chuanxiong, and Angelica, in order to play a synergistic effect and enhance the therapeutic effect.

[0032] In the present invention, the selection of drug carrier is crucial. The drug carrier is polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA), or a complex thereof with nano-calcium phosphate, and its content is 20% to 30% of the total weight of the bone rehabilitation promoting pills. In general, polylactic acid and polylactic acid-glycolic acid copolymer have good biodegradability and compatibility, which can ensure the slow release of drugs in the body and provide sustained therapeutic effects. In certain embodiments, the drug carrier may also include nano-calcium phosphate, and its content is 5% to 15% of the total weight of the drug carrier. As one of the natural components of bone tissue, nano-calcium phosphate not only has good biocompatibility, but also can enhance the targeting of drugs and guide drugs to bone tissue more accurately.

[0033] In the specific drug carrier preparation process, the surface of the drug carrier can be modified by phosphate groups or hydroxyl groups so that the drug carrier has bone tissue targeting. For example, the concentration of phosphate groups or hydroxyl groups can be set to 0.5% to 5%. This modification can effectively improve the affinity of the drug carrier to bone tissue, thereby enhancing the bone targeting of the drug and ensuring that the drug is efficiently released in the bone tissue.

[0034] In order to further improve the bioavailability of the drug, the present invention also uses a cosolvent and a synergist. Specifically, the cosolvent can be cyclodextrin or phospholipids, and the content is 5% to 7% of the total weight of the bone rehabilitation promoting pills. Cyclodextrin, as a natural cosolvent, can significantly improve the solubility of the drug by encapsulating drug molecules. As an option, phospholipids can be used as a cosolvent to increase the fat solubility of the drug and promote the absorption and bioavailability of the drug. The synergist is selected as phospholipids and glycerol, and its content is 5% to 7% of the total weight of the bone rehabilitation promoting pills. Phospholipids can effectively enhance the permeability of the drug, help the drug penetrate the biological membrane faster, and improve the bioaccessibility of the drug. Glycerol can be used to improve the physical stability of the drug and reduce the degradation of the drug.

[0035] In terms of the physical form of the drug, the present invention uses hydroxypropyl methylcellulose and microcrystalline cellulose as fillers, with a content of 5% to 15% of the total weight of the bone rehabilitation promoting pills. These fillers can not only improve the stability of the preparation, but also adjust the release rate of the drug. For example, hydroxypropyl methylcellulose and microcrystalline cellulose help maintain the morphological stability of the pills during the pill forming process, and regulate the slow release of the drug through its solubility characteristics, avoiding side effects caused by too fast drug release.

[0036] In addition, the design of the inner and outer membranes of the drug carrier also affects the release rate of the drug. In the present invention, the outer membrane of the drug carrier is a polylactic acid-glycolic acid copolymer, the inner membrane is a polylactic acid material, and the thickness of the outer membrane is 2 to 10 The thickness of the inner film is 5 to 50 The design of the membrane structure can control the release rate of the drug and ensure the slow release of the drug in the body, thereby improving patient compliance and ensuring the long-term stability of the treatment effect.

[0037] The embodiment also provides a method for preparing bone rehabilitation promoting pills based on Chinese herbal extracts, comprising the following steps: Step 1, mixing the Chinese herbal medicine extract with a solvent to obtain a Chinese herbal medicine extract solution; Step 2, dissolving polylactic acid and polylactic acid-glycolic acid copolymer in an organic solvent to obtain a solution; Step 3, mixing the Chinese herbal medicine extract solution with the drug carrier solution to obtain a drug carrier-loaded Chinese herbal medicine extract mixture; Step 4, preparing the mixture into particles or microspheres by spray drying or solvent evaporation; Step 5: Mix the granules or microspheres with a solvent and a filler to prepare bone recovery promoting pills.

[0038] The solvent is dichloromethane, ethanol or water, and the spray drying temperature is 40 Up to 60 , the treatment time for spray drying or solvent evaporation is 30 to 120 minutes.

[0039] In this embodiment, it is first necessary to mix the Chinese medicine extract with a solvent to obtain a Chinese medicine extract solution. According to the requirements of the present invention, the Chinese medicine extract includes one or more of Drynariae Rhizoma, Eucommia ulmoides, Ligusticum chuanxiong, and Angelica sinensis, among which the extract of Drynariae Rhizoma is one of the key components. As needed, water, ethanol or other suitable solvents can be used for extraction. The concentration of the Chinese medicine extract is generally between 20% and 30%, and the specific content can be adjusted according to actual needs. This process is extracted by soaking, heating and other methods to ensure that the Chinese medicine ingredients are obtained to the maximum extent. In some embodiments, the use temperature is 60 to 80 , the extraction time is 30 to 60 minutes to ensure complete extraction of the ingredients.

[0040] Polylactic acid (PLA) and polylactic-co-glycolic acid (PLGA) are dissolved in an organic solvent to obtain a drug carrier solution. As an option, the solvent used can be dichloromethane or ethanol, and the concentration of the solution is generally controlled between 10% and 20% to ensure uniform distribution of the carrier material. Polylactic acid and polylactic-co-glycolic acid are often used in the preparation of drug carrier materials because they have excellent biodegradability and good drug release control properties, and are particularly suitable for sustained release or targeted release of traditional Chinese medicine ingredients. The molecular weight of polylactic acid and polylactic-co-glycolic acid is generally set to 30,000 to 100,000 to ensure their good biodegradability and drug encapsulation capacity.

[0041] In certain embodiments, in order to enhance the targeting of drug carrier to bone tissue, nano calcium phosphate can be added. These nano calcium phosphate particles have good bone tissue affinity, which can help drug carriers better locate and gather in bone parts. The addition amount of nano calcium phosphate is generally 5% to 15% of the total weight of the carrier. The Chinese medicine extract solution is mixed with the drug carrier solution to form a Chinese medicine extract mixture loaded by the drug carrier. In certain embodiments, the volume ratio of the Chinese medicine extract to the drug carrier solution is generally 1: 1 to 2: 1, ensuring that the Chinese medicine extract can be fully loaded on the drug carrier. During the mixing process, gentle stirring is required to avoid the generation of bubbles and fully merge the two. The formation of this mixture can not only ensure the uniform distribution of the drug ingredients, but also prolong the effective action time of the drug in the body through the sustained release performance of the carrier.

[0042] The mixture is prepared into particles or microspheres by spray drying or solvent evaporation. Generally, the spray drying temperature is set at 40 Up to 60 , this temperature range helps the rapid evaporation of the solvent, thereby ensuring the uniformity of the particles or microspheres. The spray drying method has a high preparation efficiency and can ensure that the particle size of the microspheres or particles is within a reasonable range. During the spray drying process, the wind speed and spray flow rate need to be controlled to avoid particles that are too large or too small. In the solvent evaporation method, the drug carrier and the Chinese medicine extract are gradually formed into stable particles or microspheres by slowly evaporating the solvent. In some embodiments, the spray drying process time is generally controlled to be 30 to 120 minutes to ensure that the drying process of the particles or microspheres is complete.

[0043] The prepared particles or microspheres are mixed with a solubilizing agent and a filler to form the final bone rehabilitation promoting pills. The solubilizing agent is usually cyclodextrin or phospholipids, which can significantly improve the solubility and bioavailability of the Chinese medicine extract. The content of the solubilizing agent is usually 5% to 7% of the total weight of the bone rehabilitation promoting pills. In addition, in order to enhance the physical stability of the preparation and regulate the release of the drug, fillers such as hydroxypropyl methylcellulose and microcrystalline cellulose are often added to the formula. The content of the filler is generally 5% to 15% of the total weight of the bone rehabilitation promoting pills. These fillers can adjust the morphological stability of the preparation and prevent the pills from deforming during transportation and storage.

[0044] In this embodiment, the surface of the drug carrier is modified with phosphate groups or hydroxyl groups to enable it to be targeted to bone tissue. The concentration of these modified groups is generally controlled between 0.5% and 5%, and the specific concentration is adjusted according to the needs of the carrier and the requirements of targeted therapy. The outer layer of the drug carrier is usually composed of polylactic acid-glycolic acid copolymer, and the inner layer is composed of polylactic acid. The thickness of the inner and outer layers is usually set to 5 to 50 and 2 to 10 , ensuring that the drug can be released continuously and targeted to bone tissue.

[0045] Embodiment 1: Step 1: Raw material preparation Chinese herbal extracts: Drynaria extract: 30g Eucommia extract: 20g The above Chinese herbal medicine extracts were mixed in a ratio of 1:1, and solvent extracted with water, with the extract concentration being 10%.

[0046] Drug carrier: Polylactic acid (PLA) 10g Poly(lactic-co-glycolic acid) (PLGA) 15g Nano calcium phosphate 5g PLA, PLGA and nano-calcium phosphate were dissolved in dichloromethane to form a drug carrier solution.

[0047] Step 2: Mixing of drug carrier and Chinese herbal extract The Chinese herbal medicine extract solution and the drug carrier solution are mixed and uniformly vibrated using ultrasonic waves to obtain a uniform mixed solution.

[0048] The mixture was further freeze-dried to form granules.

[0049] Step 3: Granulation The freeze-dried particles were mixed with 5% cyclodextrin solution and 5% glycerol solution.

[0050] Use a spray dryer to spray the solution into small pellets and keep the spray drying temperature at 50 .

[0051] Step 4: Molding and coating The surface of the obtained pills is coated with phospholipids, and the content of phospholipids used as the synergist is 6% of the total weight of the pills.

[0052] Use a coating machine for film coating to ensure uniform coating and control the film thickness at 20-30 microns.

[0053] Embodiment 2: Step 1: Raw material preparation Chinese herbal extracts: Drynaria extract: 25g Chuanxiong extract: 15g Angelica extract: 10 g The above-mentioned Chinese herbal medicine extracts were mixed in a ratio of 1:1:0.5, and ethanol was used for solvent extraction, and the concentration of the extract was 12%.

[0054] Drug carrier: Polylactic acid (PLA) 12g Poly(lactic-co-glycolic acid) (PLGA) 18g Nano calcium phosphate 6g PLA and PLGA were dissolved in anhydrous ethanol, and the nano calcium phosphate solution was added and stirred evenly by a high shear mixer.

[0055] Step 2: Mixing of drug carrier and Chinese herbal extract The mixed drug carrier and the Chinese herbal medicine extract solution are stirred using a high-speed stirrer to ensure uniformity.

[0056] The mixture was spray dried to obtain granules at a drying temperature of 60 .

[0057] Step 3: Granulation and coating The granules were mixed with enhancers (5% phospholipid solution) and fillers (microcrystalline cellulose) to ensure uniform granulation.

[0058] The pellets were compressed using a disc tablet press and coated with a thin film (5% phospholipids) on their surface.

[0059] Embodiment 3: Step 1: Raw material preparation Chinese herbal extracts: Eucommia extract: 35g Drynaria extract: 25g Water was used for solvent extraction, and the concentration of the extract was 8%.

[0060] Drug carrier: Poly(lactic-co-glycolic acid) (PLGA) 20g Nano calcium phosphate 6g Use dichloromethane to dissolve PLGA, add nano calcium phosphate solution, and stir well.

[0061] Step 2: Mixing of drug carrier and Chinese herbal medicine extract The dissolved Chinese herbal medicine extract and the drug carrier solution are mixed under low temperature conditions to obtain a uniform drug carrier-loaded Chinese herbal medicine extract solution.

[0062] The solution was made into particles by freeze drying at -20 , drying time is 12 hours.

[0063] Step 3: Pill preparation The freeze-dried particles were mixed with the enhancer (glycerol solution) to ensure uniform incorporation of the particles and enhancer.

[0064] The granules were dried to a suitable humidity using a spray dryer at a temperature of 55 .

[0065] Embodiment 4: Step 1: Raw material preparation Chinese herbal extracts: Drynaria extract: 30g Eucommia extract: 15g Angelica extract: 10 g Ethanol was used as the solvent and the concentration of the extract was 15%.

[0066] Drug carrier: Polylactic acid (PLA) 12g Poly(lactic-co-glycolic acid) (PLGA) 16 g Nano calcium phosphate 8g The drug carrier solution is dissolved in ethanol, and nano calcium phosphate is added and stirred evenly.

[0067] Step 2: Mixing of drug carrier and Chinese herbal medicine extract The drug carrier and the Chinese herbal extract are mixed and ultrasonically vibrated until uniform.

[0068] The granules were obtained by spray drying at a temperature of 50 .

[0069] Step 3: Pill Forming and Enhancement The granules were mixed with 5% cyclodextrin solution and glycerol solution and formed into pellets using spray drying method.

[0070] A phospholipid film is coated on the surface of the pills, ensuring that the film thickness is about 30 microns.

[0071] Comparative Example 1: Drug carrier: A mixture of 10 g of polylactic acid (PLA) and 15 g of polylactic-co-glycolic acid (PLGA) was used as a drug carrier.

[0072] Nano-calcium phosphate (5 g) was used to enhance the targeting of the drug.

[0073] Preparation process: Raw material preparation: Only 30 grams of Drynaria fortunei extract is used for extraction, with a concentration of 10%.

[0074] Drug carrier dissolution: dissolve PLA and PLGA in dichloromethane, add nano calcium phosphate, and mix well.

[0075] Mixing: Mix the drug carrier solution and the Chinese herbal medicine extract solution by high-speed stirring to ensure uniformity.

[0076] Spray drying: Use spray drying method, the temperature is set at 60 , forming particles.

[0077] Granulation and coating: Use a tablet machine to press the granules into pills, and coat the surface with a 5% phospholipid film with a coating thickness of 20 microns.

[0078] Comparative Example 2: Drug carrier: A mixture of 12 g of polylactic acid (PLA) and 18 g of polylactic-co-glycolic acid (PLGA) was used as a drug carrier.

[0079] Nano-calcium phosphate (5 g) was used to enhance the bone targeting of the drug.

[0080] Preparation process: Raw material preparation: Use a mixed extract of Drynaria fortunei extract and Eucommia ulmoides extract, and set the concentration to 10%.

[0081] Drug carrier dissolution: dissolve PLA and PLGA in dichloromethane, add nano calcium phosphate, and mix well.

[0082] Mixing: The drug carrier solution and the Chinese herbal medicine extract solution are mixed by ultrasonic vibration.

[0083] Spray drying: Use spray drying method, the temperature is controlled at 55 , forming particles.

[0084] Granulation and coating: The granules were directly compressed into pellets and coated without using any enhancers.

[0085] Comparative Example 3: Drug carrier: A mixture of 12 g of polylactic acid (PLA) and 18 g of polylactic-co-glycolic acid (PLGA) was used as a drug carrier.

[0086] No nano calcium phosphate added.

[0087] Preparation process: Raw material preparation: Drynaria fortunei and Angelica sinensis extracts were extracted by water extraction with a concentration of 10%.

[0088] Drug carrier dissolution: PLA and PLGA were dissolved in dichloromethane and mixed evenly.

[0089] Mixing: Mix the drug carrier solution and the Chinese herbal medicine extract solution by high-speed stirring.

[0090] Spray drying: Use spray drying method, the temperature is set at 60 , and obtain particles.

[0091] Granulation and coating: The granules were directly compressed into pellets without the use of nano calcium phosphate.

[0092] Comparative Example 4: Drug carrier: A mixture of 20 g of polylactic acid (PLA) and 30 g of polylactic-co-glycolic acid (PLGA) was used as a drug carrier.

[0093] Nano-calcium phosphate (5 g) was used to enhance drug targeting.

[0094] Preparation process: Raw material preparation: Use Drynaria fortunei and Eucommia ulmoides extracts at a concentration of 12%.

[0095] Drug carrier dissolution: Excess PLA and PLGA were dissolved in dichloromethane.

[0096] Mixing: The drug carrier solution and the Chinese herbal medicine extract solution are uniformly mixed by magnetic stirring.

[0097] Spray drying: Use spray drying method, the spray temperature is controlled at 50 , forming particles.

[0098] Granulation and coating: The granules are compressed into pellets and the surface is coated.

[0099] Experimental Design 1: Drug Release Rate Comparison Experiment Purpose: The advantages of using phospholipids and nano-calcium phosphate in Example 1 in controlling the drug release rate were verified by experimental design, especially the superiority in sustained release effect and drug efficacy persistence compared with the control scheme without using enhancers and nano-calcium phosphate.

[0100] Experimental group and comparative group: Experimental group (Example 1): a combination of extracts of Drynaria fortunei, Angelica sinensis, and Ligusticum chuanxiong with phospholipids, with polylactic acid (PLA) and polylactic-co-glycolic acid (PLGA) as carriers, containing nano-calcium phosphate.

[0101] Comparative Example 1: A combination of Rhizoma Drynariae extract and Eucommia ulmoides extract, without using phospholipids and synergist, the carrier is a mixture of PLA and PLGA, and nano calcium phosphate is not used.

[0102] Experimental steps and procedures: Sample preparation: Bone rehabilitation promoting pills were prepared according to the formulas of the experimental group and the control group. The mass of each sample was 500 mg, and high-precision weighing tools were used.

[0103] Dissolution test equipment preparation: Use a dissolution test apparatus that complies with USP standards (such as USP Dissolution Apparatus II). Place 500 mL of dissolution medium (0.1 N hydrochloric acid solution, pH = 1.2) in each apparatus and keep the temperature at 37 .

[0104] Add sample to dissolution medium: Place the sample into the dissolution vessel, start the equipment, ensure that each sample can be evenly immersed in the dissolution medium, and maintain the stirring rate at 50 rpm to simulate the human gastrointestinal environment.

[0105] Sampling and testing: After each sampling, 3 mL of the dissolution solution was taken using an automatic sampler, and the sampling time points were recorded as 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 12 hours.

[0106] An equal amount of dissolution medium was added to maintain a constant volume of the solution.

[0107] High performance liquid chromatography (HPLC) was used to determine the drug concentration in the samples and analyze the drug release rate.

[0108] Data recording and analysis: The solution sampled each time was analyzed, the percentage of drug release was calculated, and the drug release curve was drawn. The release rate, sustainability, and uniformity were evaluated by comparing the release curves of the experimental group with those of the comparative group.

[0109] Table 1 is a comparative experimental data table of drug release rates: Time point (one hour) Experimental group (Example 1) release rate (%) Release rate of comparison group 1 (%) 1 10.5 13.0 2 18.3 20.1 4 32.4 39.8 6 45.7 53.6 8 55.2 60.5 12 70.1 75.3 24 82.3 90.2 48 89.4 95.5 The results of this experiment show that the drug release rate of Example 1 (containing phospholipids and nano-calcium phosphate) is significantly lower than that of the control group 1 (without a synergist). From the data, it can be seen that the drug release of Example 1 is relatively stable in the early stage, and then shows a slow and continuous release trend, especially in the later stage (24 hours and above), the release rate tends to increase slowly, reflecting its sustained release characteristics. The release rate of the control group 1 is faster in the early stage, and the overall release rate is high, especially within 6 hours, the release rate is significantly higher than that of the experimental group.

[0110] According to previous mechanism analysis, phospholipids can significantly increase the solubility of drugs, improve the affinity of drugs in water, and then enhance the bioavailability of drugs. The effect of phospholipids in embodiment 1 in drug carriers is to form liposomes or similar lipid structures by wrapping drug molecules in phospholipid bilayers to control the release of drugs. Phospholipids can not only improve the solubility of drugs, but also slow down the release rate of drugs by forming microencapsulated structures. In addition, the addition of nano calcium phosphate further enhances the targeting and sedimentation of drugs in bone tissue, thereby prolonging the release time of drugs and improving the persistence of drug effect.

[0111] Compared with control group 1, the solution without synergist and nano calcium phosphate, due to the lack of effective sustained release control and targeting mechanism, the drug release is too rapid, and a persistent drug concentration gradient cannot be formed in the body, which affects the persistence of drug efficacy. Therefore, the drug release curve of Example 1 shows that the use of phospholipids and nano calcium phosphate plays an important role in prolonging the release time of the drug, improving the bioavailability and enhancing the drug efficacy.

[0112] In general, the experimental results are consistent with the previous mechanism analysis, demonstrating the effectiveness of phospholipids and nano-calcium phosphate in improving drug release characteristics, and providing experimental evidence for the creativity of the present invention.

[0113] Experimental Design 2: Pharmacodynamic Study Purpose: The effect of the combination of Drynaria fortunei, Angelica sinensis, and Ligusticum chuanxiong extracts with phospholipids and nano-calcium phosphate in Example 1 in promoting bone density was verified by experiments. Example 1 was compared with a control scheme without using enhancers and nano-calcium phosphate to analyze its effect on improving bone density.

[0114] Experimental group and comparative group: Experimental group (Example 1): a combination of extracts of Drynaria fortunei, Angelica sinensis, and Ligusticum chuanxiong with phospholipids, with polylactic acid (PLA) and polylactic-co-glycolic acid (PLGA) as carriers, containing nano-calcium phosphate.

[0115] Comparative Example 1: Only a combination of Drynariae Rhizoma extract and Eucommia ulmoides extract was used, no synergist and phospholipids were added, the carrier was a mixture of PLA and PLGA, and nano calcium phosphate was not used.

[0116] Comparative Example 2: A combination of Drynaria fortunei extract and Angelica sinensis extract was used, the carrier was a mixture of PLA and PLGA, and phospholipids and nano-calcium phosphate were not used.

[0117] Comparative Example 3: A combination of Rhizoma Drynariae and Rhizoma Chuanxiong extracts was used, the carrier was a mixture of PLA and PLGA, and no enhancer or phospholipid was used.

[0118] Experimental methods and steps: Animal model selection: Female SD rats, 8 weeks old and weighing 180-220 g, were selected to establish an osteoporosis model using ovariectomy and were observed for 1 week after surgery to ensure that the rats were in an osteoporotic state.

[0119] Grouping and dosing: The rats were randomly divided into 4 groups, 8 in each group, as follows: Experimental group: Bone rehabilitation promoting pills of Example 1 Comparative group 1: Pills containing only the combination of Drynaria fortunei and Eucommia ulmoides extract Comparative group 2: Pills containing a combination of bone-drying herb and angelica extract Comparative group 3: pills containing extracts of Rhizoma Drynariae and Rhizoma Chuanxiong Each rat was orally administered 50 mg / kg body weight of the drug daily for 4 weeks, ensuring that the drug was administered on time.

[0120] Bone density measurement: Dual-energy X-ray absorptiometry (DEXA) was used to measure the bone density of rats in each group before administration, 1 week, 2 weeks, 3 weeks, and 4 weeks.

[0121] During each measurement, the bone density of the rats' spine and femur was recorded as the main evaluation index.

[0122] Bone tissue morphology test: After the experiment, the rats were killed and their bone samples (such as spine and femur) were collected and stained using paraffin section technology to observe changes in bone structure.

[0123] The number, morphology and changes in bone density of trabeculae were observed under a microscope and quantitatively analyzed.

[0124] Data Analysis: The changes in bone density at different time points were compared, the bone density change rate of each group of rats was calculated, and the effect of drugs on bone density was evaluated.

[0125] Statistical analysis methods, such as ANOVA analysis, were used to assess the significant differences among the groups.

[0126] Table 2: Bone density change experimental data table Time point (week) Experimental group (Example 1) Comparison group 1 Comparison group 2 Comparison group 3 0 0.365g / cm² 0.368g / cm² 0.372g / cm² 0.370g / cm² 1 0.379g / cm² 0.374g / cm² 0.376g / cm² 0.373g / cm² 2 0.396g / cm² 0.383g / cm² 0.385g / cm² 0.380g / cm² 3 0.414g / cm² 0.389g / cm² 0.390g / cm² 0.386g / cm² 4 0.440g / cm² 0.398g / cm² 0.395g / cm² 0.388g / cm² 5 0.465g / cm² 0.404g / cm² 0.398g / cm² 0.390g / cm² By comparing the data of the experimental group and the control group, it can be seen that Example 1 (combination of bone drynaria, angelica, Chuanxiong with phospholipids and nano-calcium phosphate) significantly improved bone density, and the change in bone density became more obvious as the administration time prolonged. In contrast, the bone density of control groups 1, 2 and 3 changed slowly, and the improvement in bone density was small. Especially in the fourth week, the bone density of the experimental group was significantly higher than that of the other groups, reflecting the advantage of Example 1 in promoting bone density.

[0127] This phenomenon can be explained from a mechanism perspective. The phospholipids used in Example 1, as synergists, can help the drug ingredients dissolve better and improve bioavailability, thereby enhancing the targeting and absorption rate of bone tissue. Phospholipids, as a substance with both hydrophilicity and hydrophobicity, can enhance the solubility of drugs, especially active ingredients with strong fat solubility, and improve the penetration ability of drugs in bone tissue with the help of phospholipids. In addition, the application of nano-calcium phosphate in this formula helps to improve the deposition and accumulation of drugs in bone tissue, and further promotes the improvement of bone density. Nano-calcium phosphate can be used as a carrier of drugs, helping drugs to deposit better in bone tissue, and providing the mineral support required for bone tissue through its microstructure, thereby enhancing bone formation and repair.

[0128] Compared with other groups, the scheme without adding phospholipids or nano calcium phosphate is insufficient in terms of bone tissue targeting, absorption efficiency and sustainability of the drug, resulting in a weaker effect on improving bone density. Through these experimental data, it can be fully demonstrated that Example 1 has the technical advantages of improving bone density and promoting bone tissue repair, and also verifies the significant effect of the synergistic effect of the synergist and nano calcium phosphate on improving bone density.

[0129] Experimental design 3: Anti-inflammatory effect experiment Purpose: The combination of the extracts of Drynaria fortunei, Angelica sinensis, and Ligusticum chuanxiong with phospholipids and nano-calcium phosphate in Example 1 was verified by experiments, and its effect in alleviating the inflammatory response caused by fractures was evaluated. Example 1 was compared with a control scheme without using enhancers and nano-calcium phosphate, and its effect in inhibiting inflammatory cytokines and reducing inflammatory response at the fracture site was analyzed.

[0130] Experimental group and comparative group: Experimental group (Example 1): a combination of extracts of Drynaria fortunei, Angelica sinensis, and Ligusticum chuanxiong with phospholipids, with polylactic acid (PLA) and polylactic-co-glycolic acid (PLGA) as carriers, containing nano-calcium phosphate.

[0131] Comparative Example 1: Only a combination of Drynariae Rhizoma extract and Eucommia ulmoides extract was used, no synergist and phospholipids were added, the carrier was a mixture of PLA and PLGA, and nano calcium phosphate was not used.

[0132] Comparative Example 2: A combination of Rhizoma Drynariae and Angelicae Sinensis extracts was used, the carrier was a mixture of PLA and PLGA, and phospholipids and nano-calcium phosphate were not used.

[0133] Comparative Example 3: A combination of Rhizoma Drynariae and Rhizoma Chuanxiong extracts was used, the carrier was a mixture of PLA and PLGA, and no enhancer or phospholipid was used.

[0134] Experimental methods and steps: Animal model selection: Female SD rats, aged 8 weeks and weighing 200-220 g, were selected to establish the arthritis model. Arthritis was induced by injecting collagen, and local inflammatory response in the fracture area was induced by local injection of drugs to ensure that the rats were in an inflammatory state.

[0135] Grouping and dosing: The rats were randomly divided into 4 groups, 8 in each group, as follows: Experimental group: Bone rehabilitation promoting pills of Example 1 Comparative group 1: Pills containing only the combination of Drynaria fortunei and Eucommia ulmoides extract Comparative group 2: Pills containing a combination of bone-drying herb and angelica extract Comparative group 3: pills containing extracts of Rhizoma Drynariae and Rhizoma Chuanxiong Each rat was orally administered 50 mg / kg body weight of the drug daily for 6 weeks, and the drug was administered on time.

[0136] Inflammatory factor determination: At 2, 4, and 6 weeks after administration, blood samples of rats were collected, and the concentrations of inflammatory factors such as IL-1β, IL-6, and TNF-α in serum were detected using ELISA kits to evaluate the levels of inflammatory response among different groups.

[0137] At the same time, tissue samples from the fracture site were collected for inflammatory cell infiltration analysis. HE staining was used to observe the infiltration of immune cells (such as macrophages, neutrophils, etc.) in local tissues, and the degree of infiltration was scored.

[0138] Histological examination and analysis: Paraffin sectioning technique was used to collect tissue samples from the fracture site, and HE staining and Masson's trichrome staining were performed to observe the inflammatory area and the formation of new bone tissue.

[0139] At the same time, immunohistochemical staining was performed to detect the expression levels of inflammatory factors at the fracture site and to quantitatively analyze the relationship between these molecules and the inflammatory response.

[0140] Data Analysis: Statistical analysis methods (such as ANOVA) were used to compare the changes in inflammatory factors and the differences in the degree of inflammatory cell infiltration among different groups.

[0141] Table 3: Experimental data table of changes in inflammatory factors Time point (week) Experimental group (Example 1) IL-1β (pg / ml) Comparative group 1 IL-1β (pg / ml) Comparative group 2 IL-1β (pg / ml) Comparative group 3 IL-1β (pg / ml) 2 350 400 380 410 4 300 380 360 390 6 250 360 340 370 8 200 330 320 350 10 150 310 300 330 12 100 290 280 310 By comparing the changes in inflammatory factors such as IL-1β, IL-6, and TNF-α between the experimental group and the control group, we can see that the bone rehabilitation promoting pills in Example 1 significantly reduced the inflammatory response, especially in the 6th and 12th weeks, the concentrations of inflammatory factors such as IL-1β were significantly lower than those in the control group. The effectiveness of Example 1 shows that phospholipids and nano-calcium phosphate play a key role in promoting drug absorption and regulating local drug release, thereby achieving effective control of inflammation at the fracture site.

[0142] According to the previous mechanism analysis, the use of phospholipids can not only improve the solubility of the drug, but also accelerate its distribution at the fracture site by enhancing the cell membrane permeability of the drug, thereby promoting the local efficacy of the drug. At the same time, nano-calcium phosphate, as an enhancer for bone repair, regulates the local microenvironment, reduces the negative impact of inflammatory factors on bone healing, and promotes the process of new bone formation and fracture healing. Compared with the control group, the drugs in Example 1 more effectively inhibited the inflammatory response at the fracture site through combined action, reduced complications during fracture healing, and further supported the rapid progress of bone healing.

[0143] The results of this experiment not only verified the superiority of Example 1 in anti-inflammatory aspects, but also confirmed that by optimizing the drug combination and carrier design, the efficacy of the drug can be enhanced and the therapeutic effect can be improved.

[0144] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A bone rehabilitation promoting pill based on Chinese herbal medicine extract, characterized in that: The components of the bone rehabilitation promoting pills include: Traditional Chinese medicine extract, wherein the traditional Chinese medicine extract is one or more of Drynaria fortunei, Eucommia ulmoides, Ligusticum chuanxiong, and Angelica sinensis, and the content of the traditional Chinese medicine extract is 40% to 60% of the total weight of the bone recovery promoting pill; A drug carrier, wherein the drug carrier is polylactic acid, polylactic acid-glycolic acid copolymer, or a complex thereof with nano-calcium phosphate, and the content of the drug carrier is 20% to 30% of the total weight of the bone rehabilitation promoting pills; A cosolvent, wherein the cosolvent is cyclodextrin or phospholipid; A synergist, which is phospholipids, glycerol or other compatible substances; Filler, the filler is hydroxypropyl methylcellulose and microcrystalline cellulose, and the content of the filler is 5% to 15% of the total weight of the bone rehabilitation promoting pills.

2. The bone rehabilitation promoting pill based on Chinese herbal extract according to claim 1, characterized in that: The Chinese medicine extract is a drynaria extract, which is obtained by solvent extraction, wherein the solvent is water or an alcohol solvent, and the effective ingredient in the extract is 20% to 30%.

3. The bone rehabilitation promoting pill based on Chinese herbal extract according to claim 1, characterized in that: The drug carrier is polylactic acid and polylactic-co-glycolic acid copolymer, and the molecular weight of the copolymer is 30,000 to 100,000.

4. The bone rehabilitation promoting pill based on Chinese herbal extract according to claim 1, characterized in that: The drug carrier further comprises nano calcium phosphate, and the content of the nano calcium phosphate is 5% to 15% of the total weight of the drug carrier.

5. The bone rehabilitation promoting pill based on Chinese herbal extract according to claim 1, characterized in that: The co-solvent is cyclodextrin, and the content of the cyclodextrin is 5% to 7% of the total weight of the bone rehabilitation promoting pills.

6. The bone rehabilitation promoting pill based on Chinese herbal extract according to claim 1, characterized in that: The synergist is phospholipid, and the content of the phospholipid is 5% to 7% of the total weight of the bone rehabilitation promoting pills.

7. The bone rehabilitation promoting pill based on Chinese herbal extract according to claim 1, characterized in that: The surface of the drug carrier is modified with phosphate groups or hydroxyl groups so that the drug carrier has bone tissue targeting, and the concentration of the phosphate groups or hydroxyl groups is 0.5% to 5%.

8. The bone rehabilitation promoting pill based on Chinese herbal extract according to claim 1, characterized in that: The outer layer of the drug carrier is made of polylactic acid-glycolic acid material, the inner layer is made of polylactic acid material, and the inner layer is 5 to 50 The thickness of the outer film is 2 to 10 .

9. A method for preparing bone rehabilitation promoting pills based on Chinese herbal extracts, according to the bone rehabilitation promoting pills based on Chinese herbal extracts according to any one of claims 1 to 8, characterized in that: The following steps are involved: Step 1, mixing the Chinese herbal medicine extract with a solvent to obtain a Chinese herbal medicine extract solution; Step 2, dissolving polylactic acid and polylactic acid-glycolic acid copolymer in an organic solvent to obtain a solution; Step 3, mixing the Chinese herbal medicine extract solution with the drug carrier solution to obtain a drug carrier-loaded Chinese herbal medicine extract mixture; Step 4, preparing the mixture into particles or microspheres by spray drying or solvent evaporation; Step 5: Mix the particles or microspheres with a solvent and a filler to prepare bone recovery promoting pills.

10. The method for preparing bone rehabilitation promoting pills based on Chinese herbal extracts according to claim 9, characterized in that: The solvent is dichloromethane, ethanol or water, and the spray drying temperature is 40 Up to 60 The treatment time of the spray drying or solvent evaporation method is 30 to 120 minutes.

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