Dapsone sustained-release capsule containing plant extract and preparation process of dapsone sustained-release capsule

Abstract

The invention provides a dapsone sustained-release capsule and a preparation method thereof, the capsule contains a sustained-release solid drug pellet, the pellet is composed of a drug pellet core and an isolating layer coating, the pellet core mainly contains dapsone, and an adhesive, a filler and a lubricant are supplemented. The isolating layer coating comprises an anti-sticking agent, a water-soluble pore-foaming agent, an antistatic agent and a non-PH-dependent low-permeability polymer, so that accurate slow release of the medicine is realized. In addition, the invention also provides a scheme of adding the plant extract glycyrrhizin into the dapsone sustained-release capsule, so that the synergistic interaction is realized, and the curative effect and safety of the medicine are improved. The quality and stability of the medicine are ensured by optimizing the prescription of the medicine pill core and accurately controlling the composition of the isolating layer coating. The preparation method adopts a powder lamination method to prepare uncoated pills, and then coating is performed, so that the process is simple and suitable for industrial production. According to the dapsone sustained-release tablet, the sustained-release effect of dapsone is achieved, the treatment effect is improved by adding glycyrrhizin, and a better treatment choice is provided for patients.

Description

Technical Field

[0001] The invention belongs to the field of biomedicine, and specifically discloses a dapsone sustained-release capsule and a preparation process thereof, and further discloses a dapsone sustained-release capsule containing a plant extract. Background Art

[0002] Dapsone, such as Figure 1 As shown in the figure, it is a sulfone antibacterial agent, which has a strong antibacterial effect on Mycobacterium leprae and shows bactericidal effect at high doses. Its mechanism of action is similar to that of sulfonamide drugs, acting on the dihydrofolate synthase of bacteria and interfering with the synthesis of folic acid. The antibacterial spectrum of the two is similar, and both can be antagonized by aminobenzoic acid. This product can also be used as a dihydrofolate reductase inhibitor. In addition, this product also has an immunosuppressive effect, which may be related to the effect of inhibiting herpetiform dermatitis.

[0003] This product is absorbed quickly and completely after oral administration. The protein binding rate is 50% to 90%. After absorption, it is widely distributed in tissues and body fluids throughout the body, with the highest concentrations in the liver and kidneys. The concentration in lesional skin is 10 times higher than that in normal skin. This product is metabolized by N-acetyltransferase in the liver. Patients can be divided into slow acetylation type and fast acetylation type of dapsone. The former has a higher peak blood concentration after taking the drug, which is prone to adverse reactions, especially adverse reactions in the blood system, but the clinical efficacy has not increased. Patients with fast acetylation may need to adjust the dose when taking the drug. This product can be measured in the blood within a few minutes after oral administration, and the peak time is 2 to 6 hours, sometimes 4 to 8 hours. This product has a hepatobiliary circulation, so it is excreted slowly, and the elimination half-life is 10 hours. After stopping the drug, this product can still exist in the blood for several weeks. About 70% to 85% of the dose is excreted in the urine as the prototype and metabolites, and a small amount is excreted through feces, sweat, saliva, sputum and milk. Therefore, the previous dosage form has large fluctuations in blood concentration and a long course of treatment, making it difficult for patients to adhere to it for a long time. At the same time, due to the excessively high blood peak concentration, some peak concentration-related dapsone syndromes often occur.

[0004] This product is used in combination with other leprosy-inhibiting drugs to treat various types of leprosy and herpetiform dermatitis caused by Mycobacterium leprae. It is also used for pustular dermatosis, pemphigoid, necrotizing pyoderma, relapsing polychondritis, annular granuloma, certain skin lesions of systemic lupus erythematosus, actinomycetoma, acne vulgaris, psoriasis, and herpes zoster. It can be used in combination with trimethoprim to treat Pneumocystis. It can be used in combination with the three to prevent vivax malaria. It has great development potential.

[0005] Sustained-release capsules are a new type of drug preparation technology developed in recent years. The development of dapsone sustained-release capsules reduces the frequency of drug administration to once a day, and the blood concentration of the drug is gentle, with small fluctuations and few adverse reactions. Clinical studies have shown that patients taking sustained-release tablets have less adverse gastrointestinal and abnormal taste reactions than patients taking ordinary tablets. Dapsone API and its ordinary tablets have been included in the 2000 edition of the Chinese Pharmacopoeia. So far, there have been no patents or literature reports on the development of dapsone sustained-release capsules at home and abroad, and no products have been launched on the market. Summary of the invention

[0006] In view of the deficiencies in the prior art, the present invention provides a dapsone sustained-release capsule containing a plant extract and a preparation process thereof.

[0007] To achieve the above objectives, the present invention includes the following technical solutions:

[0008] A dapsone sustained-release capsule containing plant extracts contains sustained-release solid drug pellets. The drug pellets have a diameter of 0-10 mm and are structurally divided into a drug pellet core and an isolation layer coating. The drug pellet core contains dapsone.

[0009] Furthermore, in the above-mentioned dapsone sustained-release capsule containing plant extracts, the drug pellet core is made by mixing a main drug and auxiliary materials; the main drug is dapsone; and the auxiliary materials are a binder, a filler, and a water-soluble lubricant.

[0010] Furthermore, in the above-mentioned dapsone sustained-release capsule containing plant extracts, the binder is hydroxypropyl methylcellulose, the filler is microcrystalline cellulose and powdered sugar, and the lubricant is sodium lauryl sulfate.

[0011] Furthermore, in the above-mentioned dapsone sustained-release capsule containing plant extracts, the isolation layer coating contains an anti-adhesive agent, a water-soluble pore-forming agent, an antistatic agent and a pH-independent low-permeability polymer.

[0012] Furthermore, in the above-mentioned dapsone sustained-release capsule containing plant extracts, the anti-adhesive in the isolation layer coating is talcum powder, the water-soluble pore-forming agent is polyethylene glycol 6000, the antistatic agent is sodium dodecyl sulfate, and the pH-independent low-permeability polymer is methacrylate copolymer or ethyl cellulose.

[0013] Furthermore, in the above-mentioned dapsone sustained-release capsule containing plant extract, the prescription of the drug pellet core is:

[0014]

[0015] Furthermore, the dosage of the isolation layer coating material per 500g of drug pellets of the above-mentioned dapsone sustained-release capsule containing plant extracts is as follows:

[0016] Methacrylate copolymer 12-90g

[0017] Talc 6-90g

[0018] Polyethylene glycol 0.2-3.0g

[0019] Sodium dodecyl sulfate 0.1-0.8g

[0020] The coating material contained in the isolation layer of the micropills accounts for 1.0-10wt% of the weight of the micropills.

[0021] The invention also discloses a preparation method of phenylsulfone sustained-release capsules, which comprises the following steps: preparing a plain pill by adopting a powder layering method, and then coating the plain pill.

[0022] Furthermore, the present invention also discloses a dapsone sustained-release capsule containing a plant extract, characterized in that glycyrrhizin, a plant extract, is added to the main drug of the dapsone sustained-release capsule.

[0023] Furthermore, in the above-mentioned dapsone sustained-release capsule containing plant extract, the prescription amount of glycyrrhizin is 1-100 mg.

[0024] Furthermore, the present invention also discloses the use of the above-mentioned dapsone sustained-release capsule containing plant extracts in the preparation of a medicine for treating psoriasis.

[0025] Compared with the prior art, the present invention has the following beneficial effects:

[0026] The beneficial effects of the above technical solution can be summarized as follows:

[0027] (1) Sustained release effect:

[0028] By adopting the design of sustained-release solid drug pellets, the dapsone sustained-release capsule can achieve slow release of drugs, thereby maintaining a stable concentration of drugs in the body, reducing the number of medications, and improving the convenience of medication for patients. The use of an isolation layer coating further enhances the sustained-release effect. By controlling the composition and dosage of the coating material, the release rate of the drug can be precisely adjusted to meet different treatment needs.

[0029] (2) Synergy:

[0030] Adding plant extract glycyrrhizin to dapsone sustained-release capsules not only enriches the therapeutic ingredients of the drug, but also achieves synergistic effects between glycyrrhizin and dapsone in treatment. Glycyrrhizin, as a natural product with multiple biological activities, can enhance the therapeutic effect of dapsone in psoriasis and improve the efficacy and safety of the drug.

[0031] (3) Optimize drug pellet prescription:

[0032] By carefully selecting the ratio of the main drug and excipients, such as dapsone, microcrystalline cellulose, powdered sugar and sodium lauryl sulfate, the stability and processability of the drug pellet core are ensured, which also helps to achieve uniform distribution of the drug and sustained-release effect.

[0033] (4) Precise control of isolation layer coating:

[0034] The selection and usage of anti-adhesives, water-soluble pore-forming agents, antistatic agents and pH-independent low-permeability polymers in the isolation layer coating are precisely calculated to ensure the stability and permeability of the coating layer, thereby accurately controlling the release rate of the drug.

[0035] (5) Feasibility of the preparation method:

[0036] The method adopts a powder layering method to prepare the vegetarian pills and then coats the vegetarian pills. The method has simple process, convenient operation, is suitable for industrial production, and can ensure the quality and stability of the drug.

[0037] In summary, this technical solution not only achieves the sustained-release effect of dapsone, but also achieves synergistic enhancement by adding glycyrrhizin in the further technical solution, thereby improving the therapeutic effect and safety of the drug. At the same time, the optimized drug pellet core prescription and precise isolation layer coating control also ensure the quality and stability of the drug, providing a better choice for the treatment of patients. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 Dapsone structural formula;

[0039] Figure 2 Release of dapsone at different coating amounts. DETAILED DESCRIPTION

[0040] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. 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.

[0041] The preparation of the dapsone sustained-release capsule of the present invention is mainly a preparation method of the sustained-release capsule (pellet) of the content thereof.

[0042] The preparation methods of the micropellets (pellets) include several conventional methods such as powder layering, suspension drug application, fluidized bed granulation, etc. The equipment used is also commonly used equipment, such as centrifugal pan coating granulator, fluidized bed granulation coating machine, non-porous or porous high-efficiency film coating pan, etc.

[0043] The dapsone sustained-release capsule of the present invention is a micro-pellet (small pellet) capsule. The micro-pellet composition is

[0044] Dapsone 4-400 mg, microcrystalline cellulose 20-200 mg, and powdered sugar 5-150 mg are used as diluents, sodium lauryl sulfate 0.1 mg-1.5 mg is used as a surfactant, and an appropriate amount of hydroxypropyl methylcellulose is used as a binder.

[0045] The coating formulation is based on 12-90 g of methacrylate copolymer as a pH-independent low-permeability polymer, 6-90 g of talc (1250 mesh) as an anti-sticking agent, 0.2-3.0 g of polyethylene glycol 60000 as a pore-forming agent, and 0.1-0.8 g of sodium dodecyl sulfate as an antistatic agent.

[0046] The preparation method of the dapsone sustained-release capsule of the present invention is to prepare a plain pill by a powder layering method, and then coat the plain pill. After investigation, different coating amounts have a great influence on the release of dapsone, as shown in Table 1 and Figure 2 is the release rate of dapsone at different coating amounts.

[0047] Table 1 Release of dapsone at different coating amounts

[0048]

[0049] Example 1

[0050] The following are examples of the production method ratios of the present invention.

[0051] (1) Preparation of mother core (blank micropellet core):

[0052] Preparation: Commercially available blank pellets can be used, or they can be prepared using a centrifugal coating granulator, a high-speed stirring granulator, an extrusion spheronizer or a fluidized bed granulator.

[0053] (2) Prescriptions containing pill cores:

[0054]

[0055] Preparation: Weigh 400 g of 40-mesh mother core and place it in the material chamber of a centrifugal coating granulator or a fluidized bed coating granulator. Add dapsone powder, powdered sugar, microcrystalline cellulose and sodium lauryl sulfate mixed powder (120 mesh) according to the prescription ratio and place it in the solid feeding chamber. Use 5% hydroxypropyl methylcellulose aqueous solution as a binder and start the centrifugal coating granulator or fluidized bed granulator coating machine.

[0056] (3) Dosage for coating 500g of drug-containing pellets:

[0057] Coating liquid prescription:

[0058]

[0059] Liquid preparation: Take the prescribed amount of Eudragit NE 30D aqueous dispersion, talcum powder (1250 mesh), sodium lauryl sulfate, polyethylene glycol and water, mix and stir evenly to use as the coating liquid.

[0060] Preparation: Place the drug-containing pellets in a centrifugal coating granulator or fluidized bed granulator for coating.

[0061] The above-mentioned drug-containing coated micropellets can be filled into ordinary capsules.

[0062] Example 2

[0063] 20 g of plant extract glycyrrhizin was added to the pill core formula of Example 1. The remaining auxiliary materials and preparation method were the same as those of Example 2 to prepare dapsone sustained-release capsules containing plant extracts.

[0064] Test Case

[0065] The following test was conducted to evaluate the therapeutic effects of dapsone and dapsone containing glycyrrhizin on skin lesions in a quimod-induced mouse psoriasis model.

[0066] Experimental method: Female BALB / c mice were randomly divided into 4 groups according to body weight, including a negative control group (oral administration of saline), Example 1 group, Example 2 group, and glycyrrhizin group; each group had 10 mice. Two days before modeling, skin preparation was performed; 40 mg of imiquimod was applied to the prepared skin area every morning for 3 consecutive days to induce psoriasis-like skin lesions and successfully establish the model.

[0067] Drug administration: The four groups of experimental mice were gavaged every morning from the 4th day, with normal saline, normal saline solution containing 2 mg of dapsone, normal saline solution containing 2 mg of dapsone + 0.5 mg of glycyrrhizic acid, and normal saline solution containing only 0.5 mg of glycyrrhizic acid; for 10 consecutive days. During the drug administration period, the degree of skin damage on the back of the mice was scored in terms of scales, skin thickening, and erythema according to the "Psoriasis Area and Severity Index (PASI)" scoring criteria.

[0068] The scoring criteria are as follows: 0 point, no symptoms; 1 point; mild symptoms; 2 points, moderate symptoms; 3 points, moderate to severe symptoms; 4 points, severe symptoms. The PASI total score (0-72 points, the higher the score, the more severe) was calculated to characterize the incidence of psoriasis-like skin lesions and the therapeutic effect of drugs. The results are shown in Table 2. The daily scores are the average scores of the same group.

[0069] Table 2 PASI total score

[0070]

[0071]

[0072] From the data in Table 2 above, it can be seen that the combined use of dapsone and glycyrrhizin has a better therapeutic effect on psoriasis-like skin lesions in mice than the use of dapsone or glycyrrhizin alone, and is much better than the negative control. This fully demonstrates that dapsone and glycyrrhizin have a potential synergistic effect, which has not been disclosed in previous literature, suggesting that the above-mentioned pharmaceutical composition (dapsone + glycyrrhizin) has a potential pharmaceutical use for treating psoriasis.

[0073] The above are limited to several preferred embodiments of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the present invention. It should be pointed out that for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. A dapsone sustained-release capsule, characterized in that: The capsule contains sustained-release solid drug pellets, the diameter of which is 0-10 mm, and the pellets are structurally divided into a drug pellet core and an isolation layer coating; the drug pellet core contains dapsone.

2. The dapsone sustained-release capsule according to claim 1, characterized in that The drug pill core is prepared by mixing a main drug and auxiliary materials; the main drug is dapsone; and the auxiliary materials are a binder, a filler and a lubricant soluble in water.

3. The dapsone sustained-release capsule according to claim 2, characterized in that: The binder is hydroxypropyl methylcellulose, the filler is microcrystalline cellulose and powdered sugar, and the lubricant is sodium lauryl sulfate.

4. The dapsone sustained-release capsule according to claim 1, characterized in that: The isolation layer coating contains an anti-adhesive agent, a water-soluble pore-forming agent, an antistatic agent and a pH-independent low-permeability polymer.

5. The dapsone sustained-release capsule according to claim 4, characterized in that The anti-adhesive in the isolation layer coating is talcum powder, the water-soluble pore-forming agent is polyethylene glycol 6000, the antistatic agent is sodium dodecyl sulfate, and the pH-independent low-permeability polymer is methyl methacrylate copolymer or ethyl cellulose.

6. The dapsone sustained-release capsule according to claim 1, characterized in that The prescription of the drug pill core is: Dapsone 4-400 mg Microcrystalline cellulose 20-200mg Powdered sugar 5-150mg Sodium dodecyl sulfate 0.1-1.5mg.

7. The dapsone sustained-release capsule according to claim 1, characterized in that The dosage of the isolation coating material for each 500g of drug pellets is as follows: Methacrylate copolymer 12-90g Talc 6-90g Polyethylene glycol 0.2-3.0g Sodium dodecyl sulfate 0.1-0.8g The coating material contained in the isolation layer of the micropills accounts for 1.0-10wt% of the weight of the micropills.

8. The method for preparing the dapsone sustained-release capsule according to any one of claims 1 to 7, characterized in that: The following steps are involved: The vegetarian pills are prepared by a powder layering method and then coated.

9. A dapsone sustained-release capsule containing a plant extract, characterized in that: Add glycyrrhizin, a plant extract, to the main drug of the dapsone sustained-release capsule as described in any one of claims 1 to 7.

10. The dapsone sustained-release capsule containing a plant extract according to claim 8, characterized in that: The prescription amount of the glycyrrhizic acid glycoside is 1-100 mg.

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