Gentiopicroside microporous osmotic pump tablet and preparation method thereof

Abstract

The invention discloses a gentiopicroside microporous osmotic pump tablet and a preparation method thereof, and the preparation method comprises the following steps: 1) preparing a medicine-containing tablet core: weighing 40-50% of gentiopicroside, 20-30% of osmotic pressure active substance, 20-39% of filler and 1-2% of lubricant according to weight ratio, granulating and tabletting to obtain the medicine-containing tablet core; 2) preparing a coating solution: weighing 2%-4% of ethyl cellulose, 0.2% of a plasticizer and 1%-3% of a pore-foaming agent according to a weight ratio, and dissolving in an organic solvent to prepare the coating solution; and 3) coating, wherein the weight of the coating is increased by 5-15% of the weight of the tablet-containing core. According to the gentiopicroside microporous osmotic pump tablet disclosed by the invention, the coating film controls the release of the medicine, the permeability of the coating film is changed by adding the pore-foaming agent, so that the medicine is released from the coating film, and the dosage of the pore-foaming agent determines the medicine release rate; according to the dosage form, the retention time of gentiopicroside in the body can be prolonged, and the treatment effect of gentiopicroside can be fully exerted.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and particularly to a gentiopicroside microporous osmotic pump tablet and a preparation method thereof. Background Art

[0002] Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease. When it occurs, the immune system attacks the joints and the cushioning tissues within them, as well as the connective tissues in many other parts of the body, such as blood vessels and lungs. The clinical manifestations are joint swelling, stiffness, pain, and in severe cases, it can cause various complications such as cardiovascular, pulmonary, and skeletal problems. In China, the prevalence of RA is approximately 0.32%-0.36%, and the incidence in women is higher than that in men. The condition of RA recurs and is difficult to cure. Although it does not pose a major threat to the patient's life, it seriously affects the patient's daily life and social activities, bringing a heavy mental and economic burden to the patient and their family. The pathogenesis of rheumatoid arthritis is still in the exploratory stage, and the currently speculated pathogenesis is factors such as immune cells, cytokines, genetics, and the environment. (Safirin S, et al. Global, regional and national burden of rheumatoid arthritis 1990-2017: a systematic analysis of the Global Burden of Disease study 2017. Ann. Rheumatol. Dis. 2019, 78(11), 1463-1471.)

[0003] Drugs for the treatment of rheumatoid arthritis include non-steroidal anti-inflammatory drugs, antirheumatic drugs, glucocorticoids, and biological agents. Non-steroidal anti-inflammatory drugs act by inhibiting cyclooxygenase, restricting the synthesis of prostacyclin, and thus playing a role. They are the first-line drugs for the treatment of RA. Traditional anti-inflammatory drugs such as aspirin and diclofenac may cause systemic adverse reactions due to their selectivity for COX. Selective COX-2 inhibitors such as nabumetone and celecoxib have significantly improved side effects compared to traditional anti-inflammatory drugs, but occasionally have cardiovascular adverse reactions. Representative drugs of antirheumatic drugs include methotrexate, leflunomide, hydroxychloroquine, gold preparations, etc. These drugs can prevent joint cartilage damage and reduce systemic complications, but they have a slow onset of action and side effects such as digestive tract problems, abnormal liver function, and bone marrow suppression, which affect their long-term use. Glucocorticoids have a rapid onset of action and significant effects, but they cannot cure RA and can also induce adverse reactions such as osteoporosis, infection, and atherosclerosis. Biological agents are an effective means for the treatment of RA, including TNF-α inhibitors, ILs, B cell depleting agents, T cell blockers, etc. However, their excessive inhibition of immune function may lead to infections and even cause a certain degree of immune tolerance, and they are very expensive. (Yang Qin, et al. Research progress on drug and surgical treatment of rheumatoid arthritis [J]. Chinese Archives of Traditional Chinese Medicine, 2023, 41(1): 133-136.)

[0004] Traditional Chinese medicine has the advantages of multiple components, multi-target synergy, and low toxicity and side effects. Currently, it has become one of the hotspots for the research and development of new anti-RA drugs. Single Chinese herbs commonly used for the treatment of RA include Sinomenium acutum, Tripterygium wilfordii, Paeonia lactiflora, Curcuma longa, and Aconitum carmichaelii, etc. Chinese medicine compound prescriptions and proprietary Chinese medicines include Baihu Jia Guizhi Decoction, Huangqi Guizhi Wuwu Decoction, Compound Fengshining Capsule, Compound Qixiong Granule, Hanshibi Tablets, Huoluo Xiaolingdan, etc. (Yang Qin, Yang Jinfeng, Yang Yutao, et al. Research progress on drug and surgical treatment of rheumatoid arthritis [J]. Chinese Archives of Traditional Chinese Medicine, 2023, 41(1): 133-136.)

[0005] Gentianoside is the main component of Gentiana scabra and Gentiana macrophylla, plants of the genus Gentiana in the Gentianaceae family, and belongs to secoiridoid compounds. Pharmacodynamic studies have shown that gentianoside has a series of pharmacological activities such as anti-inflammatory and analgesic effects, liver and gallbladder protection, stomachic function, anti-tumor, antioxidant, and blood pressure reduction. Some literature shows that gentianoside inhibits the phosphorylation of P38, ERK, and JNK in the MAPKs pathway, reduces the expression of COX-2, and decreases the production of PGE2 to achieve anti-inflammatory effects, and is expected to become a new type of COX-2 selective inhibitor. Wang et al. proved that gentianoside can inhibit the ROS-NF-κB-NLRP3 axis to alleviate RA symptoms. The results of relevant experimental studies show that gentianoside effectively inhibits the generation of osteoclasts in bone marrow macrophages (BMMs) stimulated by receptor activator of nuclear factor-κB ligand (RANKL).

[0006] (Chen F,et al.Gentiopicroside inhibits RANKL-induced osteoclastogenesis by regulating NF-kappaB and JNK signaling pathways[J].Biomedicine&pharmacotherapy=Biomedecine&pharmacotherapie.)2018;100:142-6)

[0007] In summary, gentiopicroside has good preventive and therapeutic effects on RA. Its mechanisms involve multiple aspects, including anti-inflammatory, inhibiting abnormal proliferation of synovial fibroblasts, anti-bone destruction, anti-depression and anti-obesity, and are related to signal pathways and key targets such as p38MAPK, NF-κβ, JNK, β-catenin-BMP2, Bcl-2, and MMP. (Li Peihao, et al. Research progress on the mechanism of gentiopicroside in the treatment of rheumatoid arthritis[J]. Chinese Archives of Traditional Chinese Medicine, 2023, 41(2): 154-157, 273.)

[0008] Water-soluble drugs have too strong polarity and low permeability, which is not conducive to drug absorption. Methods to improve the bioavailability of water-soluble drugs include preparing phospholipid complexes, liposomes, self-microemulsion systems, adding penetration enhancers, and pharmaceutical means. Gentiopicroside phospholipid complexes and self-microemulsion systems can significantly improve the bioavailability of gentiopicroside (Tong Yingpeng, et al. Preparation, Characterization, and In Vivo Evaluation of Gentiopicroside-Phospholipid Complex (GTP-PC) and Its Self-Nanoemulsion Drug Delivery System (GTP-PC-SNEDDS)[J]. Pharmaceuticals, 2023, 16(1): 1-19.). Gentiopicroside liposomes prepared by double emulsion method and reverse phase evaporation method have good encapsulation efficiency. These all improve bioavailability by reducing polarity. The average release rate of gentiopicroside sustained-release dropping pills is 29.16% at 2 h, 60.33% at 6 h, and 90.59% at 12 h, indicating that gentiopicroside dropping pills have a certain sustained-release effect to a certain extent. Compared with dropping pills, tablets have the advantages of large drug loading, better dissolution rate and bioavailability.

[0009] Osmotic pump controlled-release preparations can release drugs at a constant rate within a certain time range; their drug release is not affected by variable gastrointestinal factors such as peristalsis, pH, gastric emptying time, etc.; the correlation is good, so in vitro drug release data can be used to predict in vivo drug release; reduce the number of medications and improve compliance; avoid the large fluctuations in blood drug concentration caused by ordinary oral preparations, thereby reducing irritation and adverse reactions, greatly improving the safety and effectiveness of the drug. (Song Qiqi, et al. Prepation and in vitro evaluation of osmotic pump Lorcaserin hydrochloride controlled release tablets [J]. Chemical & Pharmaceutical Bulletin, 2022, 70 (3): 202-210.)

[0010] Gentiopicroside is highly hydrophilic and poorly lipophilic, so conventional oral preparations have absorption problems. Pharmacokinetic studies show that it is rapidly distributed, eliminated, and excreted in the body, making it difficult to exert a long-term therapeutic effect. Summary of the invention

[0011] The purpose of the present invention is to overcome the deficiencies of the prior art and provide a gentiopicroside microporous osmotic pump tablet with high bioavailability.

[0012] The second object of the present invention is to provide a method for preparing a gentiopicroside microporous osmotic pump tablet.

[0013] The technical solution of the present invention is summarized as follows:

[0014] The preparation method of gentiopicroside microporous osmotic pump tablets comprises the following steps:

[0015] 1) preparing a drug-containing tablet core: weighing 40%-50% of gentiopicroside, 20%-30% of an osmotic pressure active substance, 20%-39% of a filler and 1%-2% of a lubricant by weight, granulating and tableting to obtain a drug-containing tablet core;

[0016] 2) preparing a coating solution: weighing 2%-4% ethyl cellulose, 0.2% plasticizer, and 1%-3% porogen according to weight ratio, dissolving them in an organic solvent to prepare a coating solution;

[0017] 3) Coating: The coating weight gain is 5%-15% of the weight of the tablet core.

[0018] Preferably, the osmotically active substance is sodium chloride, potassium chloride, glucose or mannitol.

[0019] Preferably, the filler is lactose or starch.

[0020] Preferably, the lubricant is magnesium stearate or talcum powder.

[0021] Preferably, the plasticizer is diethyl phthalate, triethyl citrate or polyethylene glycol 6000.

[0022] Preferably, the pore-forming agent is polyethylene glycol 400, polyethylene glycol 4000 or polyethylene glycol 6000.

[0023] Preferably, the organic solvent is an aqueous ethanol solution with a volume concentration of 95%.

[0024] Preferably, the parameters of film coating are: the film coating temperature is 40°C ± 2°C, and the film coating rates are 2.7 mL·min -1 , and the rotation speed of the film coating pan is 20 r·min -1 , and the curing time is 12 h.

[0025] The gentiopicroside microporous osmotic pump tablets prepared by the above method.

[0026] The gentiopicroside microporous osmotic pump tablets of the present invention, the film coating controls the release of the drug, and the film coating material is ethyl cellulose, which is a semi-permeable membrane and water can pass through the semi-permeable membrane. It is often brittle when used alone, and adding a plasticizer can change the flexibility of the film coating; the addition of a pore-forming agent changes the permeability of the film coating and enables the drug to be released from the film coating. The dosage of the pore-forming agent determines the drug release rate; the dosage form of the present invention can prolong the residence time of gentiopicroside in the body and give full play to its therapeutic effect; the osmotic pump preparation is driven by osmotic pressure, can release the drug at a constant speed and persistently in the body, and is hardly affected by variable factors such as the chemical properties of the drug, the physiological conditions of the patient, and food intake. After the microporous osmotic pump tablets come into contact with water, the drug and excipients in the tablet core, as well as the pore-forming agent in the film coating, are dissolved. After the pore-forming agent is dissolved, micropores will be formed on the film. When a certain osmotic pressure is reached, the drug is released through the micropores. Compared with single-chamber osmotic pump tablets, the microporous osmotic pump tablets do not need to be perforated, avoiding the sudden release of the drug caused by the blockage of a single drug release hole or local high concentration. Description of the Drawings

[0027] Figure 1 It is the in vitro release curve graph of gentiopicroside microporous osmotic pump tablets with different pore-forming agents.

[0028] Figure 2 It is the influence of the dosage of the pore-forming agent on the release of gentiopicroside microporous osmotic pump tablets.

[0029] Figure 3 It is the influence of the film coating weight gain on the release of gentiopicroside microporous osmotic pump tablets.

[0030] Figure 4 It is the influence of the film coating solution concentration on the release of gentiopicroside microporous osmotic pump tablets. Detailed Embodiments

[0031] Gentiopicroside CAS#: 20831-76-9

[0032] The present invention will be further described below through specific embodiments.

[0033] Example 1

[0034] A method for preparing gentiopicroside microporous osmotic pump tablets, comprising the following steps:

[0035] 1) Preparation of the drug-containing core: Weigh 45% gentiopicroside, 25% sodium chloride (osmotic active substance), 28.5% lactose (filler), and 1.5% magnesium stearate (lubricant) according to the weight ratio;

[0036] Pass gentiopicroside, the osmotic active substance, and the filler through an 80-mesh sieve respectively, mix evenly, add an appropriate amount of wetting agent (ethanol aqueous solution with a volume concentration of 70%) to make soft materials, granulate through a 24-mesh sieve, dry at 40 °C, screen through a 20-mesh sieve, add the lubricant, and press tablets to obtain the drug-containing core;

[0037] 2) Preparation of the coating solution: Weigh 3% ethylcellulose, 0.2% diethyl phthalate (plasticizer), and 2% different pore-forming agents: polyethylene glycol 400 (PEG400), polyethylene glycol 4000 (PEG4000), and polyethylene glycol 6000 (PEG6000) according to the weight ratio, dissolve them in 94.8% organic solvent respectively to make the coating solution;

[0038] 3) Coating: The coating weight gain is 10% of the weight of the drug-containing core;

[0039] The parameters of the coating are: the coating temperature is 40 °C ± 2 °C, the coating rate is 2.7 mL·min -1 , the rotation speed of the coating pan is 20 r·min -1 , and the curing time is 12 h.

[0040] See Figure 1 , for the in vitro release curve of gentiopicroside microporous osmotic pump tablets with different pore-forming agents. The dosages of the pore-forming agent (polyethylene glycol 400) are selected as 1%, 2%, and 3% respectively, the volume contents of the solvent are 95.8%, 94.8%, and 93.8% respectively, and the others are the same as this example. See Figure 2 , Figure 2 for the effect of the dosage of the pore-forming agent on the release of gentiopicroside microporous osmotic pump tablets.

[0041] Example 2

[0042] A method for preparing gentiopicroside microporous osmotic pump tablets, comprising the following steps:

[0043] 1) Preparation of the tablet core: Weigh 40% of gentiopicroside, 30% of potassium chloride (osmotic active substance), 29% of lactose (filler), and 1% of magnesium stearate (lubricant) according to the weight ratio;

[0044] Pass gentiopicroside, the osmotic active substance, and the filler through an 80-mesh sieve respectively, mix them evenly, add an appropriate amount of wetting agent (ethanol aqueous solution with a volume concentration of 70%) to make soft materials, granulate through a 24-mesh sieve, dry at 40 °C, size through a 20-mesh sieve, add the lubricant, and press tablets to obtain the tablet core;

[0045] 2) Preparation of the coating solution: Weigh 2% of ethylcellulose, 0.2% of triethyl citrate (plasticizer), and 3% of polyethylene glycol 4000 (pore-forming agent) according to the weight ratio, dissolve them in 94.8% of organic solvent to make the coating solution;

[0046] 3) Coating: The coating weight gain is 5%, 10%, and 15% of the weight of the tablet core;

[0047] The parameters of coating are: the coating temperature is 40 °C ± 2 °C, the coating rates are 2.7 mL·min -1 respectively, the rotation speed of the coating pan is 20 r·min -1 respectively, and the curing time is 12 h.

[0048] See Figure 3 Figure 3 for the influence of coating weight gain on the release of gentiopicroside microporous osmotic pump tablets.

[0049] Example 3

[0050] A preparation method of gentiopicroside microporous osmotic pump tablets, comprising the following steps:

[0051] 1) Preparation of the tablet core: Weigh 50% of gentiopicroside, 20% of glucose (osmotic active substance), 28% of lactose (filler), and 2% of magnesium stearate (lubricant) according to the weight ratio;

[0052] Pass gentiopicroside, the osmotic active substance, and the filler through an 80-mesh sieve respectively, mix them evenly, add an appropriate amount of wetting agent (ethanol aqueous solution with a volume concentration of 70%) to make soft materials, granulate through a 24-mesh sieve, dry at 40 °C, size through a 20-mesh sieve, add the lubricant, and press tablets to obtain the tablet core;

[0053] 2) Preparation of coating solution 1: Weigh 4% of ethylcellulose, 0.2% of polyethylene glycol 6000 (plasticizer), and 1% of polyethylene glycol 4000 (pore-forming agent) according to the weight ratio, dissolve them in 94.8% of organic solvent to make the coating solution;

[0054] 3) Coating: The coating weight gain is 15% of the weight of the tablet core;

[0055] ​The parameters for film coating are as follows: the film coating temperature is 40°C ± 2°C, and the film coating rates are 2.7 mL·min -1 , the rotation speed of the coating pan is 20 r·min -1 , and the curing time is 12 h.

[0056] Preparation of coating solution 2: Weigh 3% ethylcellulose, 0.2% polyethylene glycol 6000 (plasticizer), and 1% polyethylene glycol 4000 (pore-forming agent) according to the weight ratio, and dissolve them in 95.8% organic solvent to prepare the coating solution;

[0057] Preparation of coating solution 3: Weigh 2.5% ethylcellulose, 0.2% polyethylene glycol 6000 (plasticizer), and 1% polyethylene glycol 4000 (pore-forming agent) according to the weight ratio, and dissolve them in 96.3% organic solvent to prepare the coating solution;

[0058] Preparation of coating solution 4: Weigh 2% ethylcellulose, 0.2% polyethylene glycol 6000 (plasticizer), and 1% polyethylene glycol 4000 (pore-forming agent) according to the weight ratio, and dissolve them in 96.8% organic solvent to prepare the coating solution;

[0059] See Figure 4 , Figure 4 for the effect of coating solution concentration on the release of gentiamarin microporous osmotic pump tablets.

[0060] Example 4

[0061] Method for preparing gentiamarin microporous osmotic pump tablets, comprising the following steps:

[0062] 1) Preparation of drug-containing tablet core: Weigh 49% gentiamarin, 29% mannitol (osmotic active substance), 20% starch (filler), and 2% talc powder (lubricant) according to the weight ratio;

[0063] Pass gentiamarin, osmotic active substance, and filler through a 80-mesh sieve respectively, mix evenly, add an appropriate amount of wetting agent (ethanol aqueous solution with a volume concentration of 70%) to make soft materials, granulate through a 24-mesh sieve, dry at 40°C, screen through a 20-mesh sieve, add lubricant, and press tablets to obtain the drug-containing tablet core;

[0064] 2) Preparation of coating solution: Weigh 3% ethylcellulose, 0.2% diethyl phthalate (plasticizer),

[0065] 2% polyethylene glycol 400 (pore-forming agent), and dissolve them in 94.8% organic solvent to prepare the coating solution;

[0066] 3) Film coating: The film coating weight gain is 8% of the weight of the drug-containing tablet core;

[0067] The parameters for film coating are as follows: the film coating temperature is 40°C ± 2°C, and the film coating rates are 2.7 mL·min-1 with the rotation speed of the coating pan being 20 r·min -1 and the curing time being 12 h.

[0068] Example 5

[0069] A method for preparing gentiopicroside microporous osmotic pump tablets, comprising the following steps:

[0070] 1) Preparing the drug-containing tablet core: Weigh 40% of gentiopicroside, 20% of mannitol (osmotic active substance), 39% of starch (filler), and 1% of talc powder (lubricant) according to the weight ratio;

[0071] Pass gentiopicroside, the osmotic active substance, and the filler through a 80-mesh sieve respectively, mix them evenly, add an appropriate amount of wetting agent (ethanol aqueous solution with a volume concentration of 70%) to make soft materials, granulate through a 24-mesh sieve, dry at 40°C, screen through a 20-mesh sieve, add the lubricant, and press tablets to obtain the drug-containing tablet core;

[0072] 2) Preparing the coating solution: Weigh 3% of ethyl cellulose and 0.2% of diethyl phthalate (plasticizer) according to the weight ratio,

[0073] 2% of polyethylene glycol 400 (pore-forming agent), dissolve them in 94.8% of organic solvent to make the coating solution;

[0074] 3) Coating: The coating weight gain is 10% of the weight of the drug-containing tablet core;

[0075] The parameters of coating are: the coating temperature is 40°C ± 2°C, and the coating rate is 2.7 mL·min -1 with the rotation speed of the coating pan being 20 r·min -1 and the curing time being 12 h.

[0076] The organic solvent in Examples 1, 2, 3, 4, and 5 is an ethanol aqueous solution with a volume concentration of 95%.

Claims

1. Preparation method of gentiopicroside microporous osmotic pump tablets, which is characterized in that it includes the following steps: 1) Prepare the drug-containing tablet core: Weigh 40%-50% of gentiopicroside, 20%-30% of osmotic pressure active substance, 20%-39% of filler and 1%-2% of lubricant according to the weight ratio, granulate and press to obtain the drug-containing tablet core; 2) Prepare the coating solution: Weigh 2%-4% of ethyl cellulose, 0.2% of plasticizer, and 1%-3% of pore-forming agent according to the weight ratio, dissolve in an organic solvent to form the coating solution; 3) Coating: The coating weight gain is 5%-15% of the weight of the drug-containing tablet core.

2. The preparation method according to claim 1, which is characterized in that the osmotic pressure active substance is sodium chloride, potassium chloride, glucose or mannitol.

3. The preparation method according to claim 1, which is characterized in that the filler is lactose or starch.

4. The preparation method according to claim 1, which is characterized in that the lubricant is magnesium stearate or talcum powder.

5. The preparation method according to claim 1, which is characterized in that the plasticizer is diethyl phthalate, triethyl citrate or polyethylene glycol 6000.

6. The preparation method according to claim 1, which is characterized in that the pore-forming agent is polyethylene glycol 400, polyethylene glycol 4000 or polyethylene glycol 6000.

7. The preparation method according to claim 1, which is characterized in that the organic solvent is an ethanol aqueous solution with a volume concentration of 95%.

8. The preparation method according to claim 1, which is characterized in that The parameters of the coating are as follows: the coating temperature is 40°C ± 2°C, and the coating rates are 2.7 mL·min -1 , the rotation speed of the coating pan is 20 r·min -1 , and the curing time is 12 h.

9. Gentiopicroside microporous osmotic pump tablets prepared by the method of any one of claims 1-8.

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