CN116602911A - Medicated Hollow Rectal Suppository - Google Patents

Abstract

The invention discloses a hollow rectal suppository containing medicines, belongs to the technical field of medical and health, and can solve the problem that the traditional suppository is easy to be discharged from a body. The whole medicated hollow rectal suppository is cylinder-like and consists of an outer part suppository shell and an inner part spring, and the inner part is hollow. The hollow structure can provide a fecal discharge channel, prolong the residence time of the hollow rectal plug containing the drug in the rectum, prevent the drug from being diluted by the feces and discharge along with the feces, and continuously release the drug. The length and the inner diameter of the hollow rectal suppository containing the medicine can be individually designed according to the rectum size and the treatment requirement of a patient. The curve shape of the curve-shaped suppository shell can enable the hollow rectal suppository containing the medicine to be clung to the intestinal wall, long-time retention is realized, and the structure with narrow upper part and wide lower part is beneficial to the incorporation of the rectal suppository. The inner part spring provides supporting function, so that the hollow rectal suppository containing the medicine keeps complete form, resists certain pressure, and the outer part suppository shell is tightly attached to the intestinal wall after being taken into the rectum.

Description

Medicated Hollow Rectal Suppository

technical field

The invention relates to the field of medical and health technologies, in particular to a drug-containing hollow rectal suppository.

Background technique

Rectal administration has a long history of use and is an effective alternative to oral treatment, which can exert local and systemic therapeutic effects. Among them, suppositories are the most commonly used rectal administration system, accounting for more than 98% of all rectal dosage forms. Rectal suppository is generally made of appropriate matrix and drugs, and it is a solid preparation for rectal use. It can not only be used for local treatment, exert lubricating, astringent, antibacterial, insecticidal, and local anesthesia functions, but also exert systemic therapeutic effects. Such as fever, diarrhea.

At present, rectal suppositories for clinical use basically adopt the most common rectal suppository type, that is, solid bullet structure, but this structure has poor physiological adaptability and is easily excreted with feces. For example, ibuprofen suppositories are administered rectally, which overcomes the shortcomings of oral dosage forms, and have the advantages of convenient administration and quick onset of action. However, ibuprofen suppositories melt quickly and are easily discharged from the rectum, especially for children who are difficult to control defecation. What's more, the therapeutic effect cannot be guaranteed. Therefore, finding a new type of rectal suppository suitable for the physiological characteristics of the rectum is the key to achieving good adaptability and ensuring drug efficacy.

Contents of the invention

The inventors designed and prepared a medicine-containing hollow rectal suppository, which can stay in the rectum for a long time and release medicine continuously.

The invention discloses a medicine-containing hollow rectal suppository, which is in a cylindrical shape as a whole and is composed of an outer part of a plug shell containing a polymer, a porogen and a drug, and an inner part of a spring, and is hollow inside. The outer shell is selected from straight cylindrical shells, trapezoidal shells, curved shells, preferably curved shells. The inner part spring is a spring embedded in the inner wall of the outer part of the shell.

The hollow rectal suppository containing medicine in the present invention has an internal hollow structure that can provide a passage for excreting feces, prolongs the residence time of the hollow rectal suppository containing medicine in the rectum, and prevents medicine from being diluted by feces and being discharged with feces.

The length and inner diameter of the drug-containing hollow rectal suppository of the present invention can be individually designed according to the patient's rectal size and treatment needs.

In the medicine-containing hollow rectal suppository of the present invention, the curvilinear radian of the curvilinear capsule shell can be individually designed according to the patient's rectal size and treatment needs.

The drug-containing hollow rectal suppository of the present invention has a curved capsule shell that is narrow at the top and wide at the bottom.

The drug-containing hollow rectal suppository of the present invention, wherein the curved shape of the curvilinear plug shell can make the drug-containing hollow rectal suppository closely adhere to the intestinal wall to achieve long-term retention. The narrow upper part and wider lower part of the curvilinear plug shell help to reduce the resistance when the drug-containing hollow rectal suppository is put into the rectum when the narrow end is put into the rectum first, so that it is easy to insert into the rectum and difficult to discharge.

In the drug-containing hollow rectal suppository of the present invention, the inner part of the spring can provide support for the outer part of the plug shell in vitro and in the rectum, so that the drug-containing hollow rectal suppository can maintain a complete shape and withstand a certain pressure. The shell clings to the intestinal wall.

The preparation method of the drug-containing hollow rectal suppository and the outer part of the capsule shell in the present invention is selected from the mold infusion method and the 3D printing method, preferably the mold infusion method. The 3D printing method is selected from a fused deposition type 3D printing method and an optical three-dimensional printing 3D printing method. When using the fused deposition 3D printing method to prepare the outer partial shell, the polymer, porogen, and drug are formed into a molten mixture, and then extruded from the tip of the molding device according to the model parameters designed by the computer, and deposited onto the platform layer by layer, The outer partial shell was prepared. When using the mold pouring method to prepare the outer partial shell, the polymer, porogen and drug are mixed and melted to form a solution, and then poured into the outer partial shell mold to prepare the outer partial shell of the drug-containing hollow rectal suppository. The shell mold of the outer part is a component composed of a concave mold structure and a convex mold structure. The properties can be adjusted according to the treatment needs of patients. It can be obtained by entrusting a device processing company, or it can be prepared by 3D printing. The general material is selected from high-strength metal or alloy.

In the hollow rectal suppository containing medicine in the present invention, the preparation method of the inner part spring is selected from cutting method and 3D printing method, preferably 3D printing method. The 3D printing method is selected from a fused deposition type 3D printing method and an optical three-dimensional printing 3D printing method. When using the fused deposition 3D printing method to prepare the inner part of the spring, the polymer is melted, then extruded from the tip of the molding device according to the model parameters designed by the computer, and deposited on the platform layer by layer to prepare the spring embryo, and the spring is cut with a cutter The connecting part between the wires is divided to obtain the internal partial spring.

In the drug-containing hollow rectal suppository of the present invention, the polymer is selected from the group consisting of propylene-butadiene-benzenediene copolymer (ABS), polyvinyl alcohol (PVA), polylactic glycolic acid (PLGA), polycaprolactone ( PCL), thermoplastic polyurethane (TPU), photosensitive resin, choose one of them or a combination of several polymers. The polymers used for the preparation of the outer shell are preferably polycaprolactone, polyvinyl alcohol. The polymer used for the preparation of the inner partial spring is preferably selected from thermoplastic polyurethanes, photosensitive resins.

In the drug-containing hollow rectal suppository of the present invention, the porogen is selected from sucrose, lactose, glucose, propylene glycol, glycerin, polyethylene glycol, and sodium chloride, preferably from propylene glycol, glycerin, and polyethylene glycol, and more preferably Glycerin, polyethylene glycol. Polyethylene glycol is selected from polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1000, polyethylene glycol 8000, preferably polyethylene glycol 1000, polyethylene glycol 8000. The mass ratio of the porogen in the composition of the outer shell is selected from 0.1% to 10%, preferably from 1% to 5%. The ratio of porogen has an effect on the release rate of drug from the outer partial shell.

The drug-containing hollow rectal suppository of the present invention can be selected from various drugs, and can be selected from drugs for treating various diseases, preferably selected from drugs for treating ulcerative colitis and drugs for treating epilepsy.

Drugs for treating ulcerative colitis are selected from aminosalicylic acid drugs, glucocorticoids, and immunomodulators. The aminosalicylates are selected from mesalazine, sulfasalazine, olsalazine, and balsalazide sodium. Glucocorticoid drugs are selected from budesonide, hydrocortisone, cortisone, dexamethasone, betamethasone, betamethasone dipropionate, fluticasone propionate, ciclesonide, hydrocortisone acetate, Prednisone, prednisolone, methylprednisolone, triamcinolone, methylprednisolone acetate, prednisolone acetate, dexamethasone acetate, betamethasone butyrate, triamcinolone acetonide, triamcinolone acetate, butyric acid Hydrocortisone, Diflurasolone, Halotamethasone, Clofluxasone. Immunomodulator drugs are selected from azathioprine, cyclosporine, 6-mercaptopurine, and cyclophosphamide. The drug is preferably selected from mesalazine, sulfasalazine, olsalazine, balsalazide, dexamethasone, budesonide, more preferably mesalazine, sulfasalazine, olsalazine, balsalazide , most preferably mesalazine. Correspondingly, the drug-containing hollow rectal suppository is selected from mesalazine hollow rectal suppository, sulfasalazine hollow rectal suppository, olsalazine hollow rectal suppository, balsalazide sodium hollow rectal suppository, budesonide hollow rectal suppository, hydrocortisone Pine hollow rectal suppository, cortisone hollow rectal suppository, dexamethasone hollow rectal suppository, betamethasone hollow rectal suppository, betamethasone dipropionate hollow rectal suppository, fluticasone propionate hollow rectal suppository, ciclesonide hollow rectal suppository , Hydrocortisone acetate hollow rectal suppository, prednisone hollow rectal suppository, prednisolone hollow rectal suppository, methylprednisolone hollow rectal suppository, triamcinolone hollow rectal suppository, methylprednisolone acetate hollow rectal suppository, prednisolone acetate Songlong hollow rectal suppository, dexamethasone acetate hollow rectal suppository, betamethasone butyrate hollow rectal suppository, triamcinolone acetonide hollow rectal suppository, triamcinolone acetonide hollow rectal suppository, hydrocortisone butyrate hollow rectal suppository, diacetate Difluosone hollow rectal suppository, haltamethasone hollow rectal suppository, cloflususone hollow rectal suppository, azathioprine hollow rectal suppository, cyclosporin hollow rectal suppository, 6-mercaptopurine hollow rectal suppository, cyclophosphamide hollow rectal suppository Rectal suppository, preferably selected from mesalazine hollow rectal suppository, sulfasalazine hollow rectal suppository, olsalazine hollow rectal suppository hollow rectal suppository, balsalazide sodium hollow rectal suppository, dexamethasone hollow rectal suppository, budesonide hollow rectal suppository Suppository, more preferably mesalazine hollow rectal suppository, sulfasalazine hollow rectal suppository, olsalazine hollow rectal suppository, balsalazide sodium hollow rectal suppository, most preferably mesalazine hollow rectal suppository.

Epilepsy drugs are selected from phenytoin, phenobarbital, primidone, carbamazepine, valproic acid, benzodiazepine, carbamazepine, levetiracetam, lamotrigine, oxcarbazepine, topiramate, Acetimide, zonisamide, lacosamide, gabapentin, eslicarbazepine, pregabalin, lacosamide, rufinamide, clobazam, brivaracetam, cannabidiol, phenobar Namate, preferably selected from topiramate, cannabidiol, benzonamate, rufinamide, clobazam, buvaracetam, more preferably topiramate, cannabidiol, benzonamate, rufinamide, Most preferred is cannabidiol. Correspondingly, the drug-containing hollow rectal suppository is selected from the group consisting of phenytoin hollow rectal suppository, phenobarbital hollow rectal suppository, primidone hollow rectal suppository, carbamazepine hollow rectal suppository, valproic acid hollow rectal suppository, and benzodiazepine hollow rectal suppository. Suppository, carbamazepine hollow rectal suppository, levetiracetam hollow rectal suppository, lamotrigine hollow rectal suppository, oxcarbazepine hollow rectal suppository, topiramate hollow rectal suppository, acetimide hollow rectal suppository, zonisamide hollow rectal suppository Rectal suppository, lacosamide hollow rectal suppository, gabapentin hollow rectal suppository, eslicarbazepine hollow rectal suppository, pregabalin hollow rectal suppository, lacosamide hollow rectal suppository, rufinamide hollow rectal suppository, clobazam Hollow rectal suppository, brivaracetam hollow rectal suppository, cannabidiol hollow rectal suppository, benbarnamate hollow rectal suppository, preferably selected from topiramate hollow rectal suppository, cannabidiol hollow rectal suppository, benbarnamate hollow rectal suppository, Phenamide hollow rectal suppository, clobazam hollow rectal suppository, buvaracetam hollow rectal suppository, more preferably topiramate hollow rectal suppository, cannabidiol hollow rectal suppository, benbanamate hollow rectal suppository, rufinamide A hollow rectal suppository, most preferably a cannabidiol hollow rectal suppository.

The drug-containing hollow rectal suppository of the present invention is characterized by not affecting normal defecation. By adjusting the material, length, curvature and inner diameter of the hollow suppository, individualized and precise design and preparation can be carried out, and the residence time of the hollow rectal suppository in the rectum can be controlled. . After the drug-containing hollow rectal suppository stays in the rectum for a certain period of time, the outer part of the plug shell gradually dissolves, and the inner part of the spring can be discharged from the rectum.

The hollow rectal suppository containing medicine can effectively alleviate the inflammatory response of ulcerative colitis and epilepsy, reduce the damage of colon tissue and brain tissue, and delay the disease process.

Description of drawings

Fig. 1. Design drawing (A) and actual drawing (B) of the shell mold of the outer part of the drug-containing hollow rectal suppository.

Figure 2. The physical picture of the external part of the drug-containing hollow rectal suppository (A) and the schematic diagram of the assembly process of the drug-containing hollow rectal suppository (B). F-MHS: Mesalazine hollow rectal suppository shell prepared by 3D printing; M -MHS: mesalazine hollow rectal suppository prepared by mold perfusion; CHS: cannabidiol hollow rectal suppository.

Figure 3. Infrared spectrum. See Figure 2 for descriptions of F-MHS, M-MHS, and CHS.

Figure 4. X-ray diffraction patterns. See Figure 2 for descriptions of F-MHS, M-MHS, and CHS.

Figure 5. Thermogravimetric analysis spectrum. See Figure 2 for descriptions of F-MHS, M-MHS, and CHS.

Figure 6. SEM image. See Figure 2 for descriptions of F-MHS, M-MHS, and CHS.

Figure 7. Mesalazine hollow rectal suppository drug release curve in vitro. See Figure 2 for descriptions of F-MHS and M-MHS.

Figure 8. In vitro drug release curve of cannabidiol hollow rectal suppository. See Figure 2 for CHS description.

Figure 9. X-ray images of iohexol hollow rectal suppository at different time points in the rectum of rats

Figure 10. Histopathological sections of the colorectum of rats with ulcerative colitis treated with mesalazine hollow rectal suppository

Figure 11. Inflammatory factors TNF-α (A), IL-1β (B) and IL-6 (C) in rectal tissue of rats with ulcerative colitis treated with mesalazine hollow rectal suppository. n=4, **P<0.01, **P<0.01, ***P<0.001

Figure 12. Pathological sections of the brain tissues of epileptic rats treated with cannabidiol hollow rectal suppository

Figure 13. Inflammatory factors TNF-α (A), IL-1β (B) and IL-6 (C) in brain tissue of epileptic rats treated with cannabidiol hollow rectal suppository. n=3, **P<0.01, ***P<0.001

Detailed ways

Example 1. Mesalazine Hollow Rectal Suppository

Prepare the mesalazine hollow rectal suppository shell by mold infusion: weigh 2g of polyvinyl alcohol, add 3mL of water and 2mL of glycerin, heat in a water bath, and keep stirring to obtain a paste mixture of polyvinyl alcohol, and separately take 0.08g of polyethylene glycol Add alcohol 1000, 0.32g polyethylene glycol 8000, and 0.32g mesalamine to the above-mentioned polyvinyl alcohol paste mixture, and stir well to obtain the mesalazine paste mixture; the mesalazine hollow rectal suppository mold consists of three parts , two different four die structures except for the locking structure, used to form the outer part of the mesalazine hollow rectal suppository shell, its shape is a cuboid, 70 mm long, 17 mm wide, and 6 mm thick. Composed of two incomplete symmetrical spherical spaces, there are 5 narrowest and widest positions from top to bottom, and the distances are 7 mm, 9.2 mm, 8.5 mm, 11.2 mm, and 6.6 mm, one for forming Mesalazine hollow rectal suppository consists of 4 cylindrical structures with a hollow structure inside. The bottom is cuboid, 70 mm long, 16 mm wide, and 2 mm thick. The diameter of the cylindrical structure is 6.5 mm, the height is 17 mm, and the spacing is 7.4 mm; Pour the paste mixture into the mesalazine hollow rectal suppository mold, let it stand at minus 20°C for more than 2 hours, and demould to obtain the curved mesalazine hollow rectal suppository shell; use 3D printing to prepare the mesalazine hollow rectal suppository Partial spring: modeled by 3D design software, design the internal partial spring structure, with a wire diameter of 0.85mm, a coil diameter of 5.60mm, and a pitch of 0.88mm, convert it into a 3D printer-recognizable parameter file, and load the thermoplastic polyurethane extrusion wire into the fusion deposition 3D printer, printing parameters include nozzle temperature 200°C, hot bed temperature 30°C, printing speed 70mm/s, the spring embryo is prepared, and the connection part between the spring wires is divided with a knife to obtain the internal spring; mesalazine hollow rectum Assembling the plug: compress the mesalazine hollow rectal plug shell and the internal spring of the mesalazine hollow rectal plug laterally, insert one end into the opening of the mesalazine hollow rectal plug shell, block one end of the plug shell, and rotate the spring plug continuously Insert until the spring is completely inserted into the outer part of the plug shell to obtain the mesalazine hollow rectal plug.

The 3D printing design of the hollow rectal plug shell mold is shown in Figure 1A, and the actual photo is shown in Figure 1B. The upper and middle photos are two different 4 die structures except for the locking structure, and the lower photo is 4 cylindrical structures. .

The appearance photo of the mesalazine hollow rectal suppository is shown in the M-MHS in Figure 2A. A schematic diagram of the assembly of the mesalazine hollow rectal suppository is shown in Figure 2B.

The above-mentioned polyvinyl alcohol can be replaced with other polymers, the porogen glycerin, polyethylene glycol 1000, and polyethylene glycol 8000 can be replaced with other porogens, and mesalazine can be replaced with other drugs. The proportions of the above components in the hollow rectal suppository can be properly adjusted according to specific conditions. The drug-containing hollow rectal suppository can be obtained through the above process.

Example 2. Mesalazine Hollow Rectal Suppository

Preparation of mesalazine hollow rectal suppository shell by fused deposition 3D printing method: Weigh 1g of polyethylene glycol 1000, heat in a water bath at 37°C, add 1g of mesalazine and 8g of polyvinyl alcohol, stir well, and dry at 50°C for 3 hours , after placing it at room temperature, make a small block, put it into the trough of the extruder, and obtain a mesalazine extruded wire with a diameter of about 1.75 mm after extrusion; through 3D design software modeling, the shell structure of the outer part is designed as The curved shell structure is composed of a hollow cylinder with a diameter of 7 mm and a curved shell. There are 5 narrowest and widest positions of the curved shell from top to bottom, and the distances are 7 mm, 9.4 mm, 9 mm, 10 mm, 7 mm, converted into a 3D printer-recognizable parameter file, select appropriate parameters to print, and obtain a curved mesalazine hollow rectal suppository shell; use 3D printing to prepare the internal spring of the mesalazine hollow rectal suppository: Through 3D design software modeling, design the internal partial spring structure, the wire diameter is 0.85mm, the coil diameter is 5.60mm, and the pitch is 0.88mm, and it is converted into a 3D printer-recognizable parameter file, and the thermoplastic polyurethane extruded wire is loaded into the fused deposition 3D printer. Printing parameters include nozzle temperature 200°C, hot bed temperature 30°C, printing speed 70mm/s, the spring embryo is prepared, and the connecting part between the spring wires is divided with a cutter to obtain the internal spring; the assembly of the mesalazine hollow rectal suppository : Compress the mesalazine hollow rectal suppository shell and the internal spring of the mesalazine hollow rectal suppository laterally, insert one end into the opening of the mesalazine hollow rectal suppository shell, block one end of the shell, and insert the spring continuously until The spring was completely inserted into the outer partial plug shell to obtain a mesalazine hollow rectal plug.

The appearance photo of mesalazine hollow rectal suppository is shown in F-MHS in Figure 2A. A schematic diagram of the assembly of the mesalazine hollow rectal suppository is shown in Figure 2B.

The above-mentioned polyvinyl alcohol can be replaced with other polymers, the porogen glycerin and polyethylene glycol 1000 can be replaced with other porogens, and mesalazine can be replaced with other drugs. The proportions of the above components in the hollow rectal suppository can be properly adjusted according to specific conditions. The drug-containing hollow rectal suppository can be obtained through the above process.

Example 3. Cannabidiol hollow rectal suppository

Prepare the cannabidiol hollow rectal suppository shell by mold infusion: weigh 2g of polyvinyl alcohol, add 3mL of water and 2mL of glycerin, heat in a water bath, and keep stirring to obtain a paste mixture of polyvinyl alcohol, and take 0.08g of polyethylene glycol respectively Add alcohol 1000, 0.32g polyethylene glycol 8000, and 0.32g cannabidiol to the above-mentioned polyvinyl alcohol paste mixture, and stir well to obtain a cannabidiol paste mixture; the cannabidiol hollow rectal suppository mold consists of three parts , two 4 die structures except for the locking structure, used to form the external part of the cannabidiol hollow rectal suppository shell, its shape is a cuboid, 70 mm long, 17 mm wide, and 6 mm thick, and the concave part is up and down Composed of two incomplete symmetrical spherical spaces, there are 5 narrowest and widest positions from top to bottom, and the distances are 7 mm, 9.2 mm, 8.5 mm, 11.2 mm, and 6.6 mm, one for forming Cannabidiol hollow rectal suppository has 4 cylindrical structures with a hollow structure inside, the bottom of which is a cuboid, 70 mm long, 16 mm wide, and 2 mm thick. The diameter of the cylindrical structure is 6.5 mm, the height is 17 mm, and the distance is 7.4 mm; Pour the paste mixture into the cannabidiol hollow rectal suppository mold, let it stand at minus 20°C for more than 2 hours, and release the mold to obtain the curved cannabidiol hollow rectal suppository shell; use 3D printing to prepare the cannabidiol hollow rectal suppository Partial spring: modeled by 3D design software, design the internal partial spring structure, with a wire diameter of 0.85mm, a coil diameter of 5.60mm, and a pitch of 0.88mm, convert it into a 3D printer-recognizable parameter file, and load the thermoplastic polyurethane extrusion wire into the fusion deposition 3D printer, printing parameters include nozzle temperature 200°C, hot bed temperature 30°C, printing speed 70mm/s, the spring embryo is prepared, and the connecting part between the spring wires is divided with a knife to obtain the inner part of the spring; cannabidiol hollow rectum Assembly of the suppository: compress the cannabidiol hollow rectal suppository shell and the internal spring of the cannabidiol hollow rectal suppository laterally, insert one end into the opening of the cannabidiol hollow rectal suppository shell, block one end of the suppository shell, and continuously rotate the spring plug Insert until the spring is completely inserted into the outer part of the plug shell to obtain the cannabidiol hollow rectal plug.

The appearance photo of cannabidiol hollow rectal suppository is shown in CHS in Figure 2A. The assembly diagram of the cannabidiol hollow rectal suppository is shown in Figure 2B.

Experimental Example 1. Investigation on the Properties of Mesalazine Hollow Rectal Suppository and Cannabidiol Hollow Rectal Suppository

Materials: Mesalazine hollow rectal suppository shells prepared according to Example 1 and Example 2, including M-MHS shells and F-MHS shells, cannabidiol hollow rectal suppository shells prepared according to Example 3, namely CHS Capsid, blank hollow rectal suppository (preparation method is the same as that in Example 1 except that mesalazine is not added), mesalamine, and cannabidiol.

Method: The samples were analyzed by Fourier transform infrared spectrometer (FTIR) with a scanning range of 3600cm ^-1 ~ 600cm ^-1 and a resolution of 2cm ^-1 . The samples were analyzed by Empyrean X-ray powder diffractometer, the conditions were Cu target, X-ray wavelength 0.15406nm, tube voltage 40kV, tube current 40mA, step size 0.02°, scanning speed 5°/min, scanning range 5°～50 °. Samples were taken and measured by a synchronous thermal analyzer (STA 6000), under the conditions that the heating rate was 10°C/min, and the temperature rising range was 30°C-400°C. The surface and cross-section of the mesalazine hollow rectal suppository shell and the cannabidiol hollow rectal suppository shell were taken for scanning electron microscope (CUBE2, EM Cote, South Korea) observation and photographed records.

Results: Infrared spectra showed that the characteristic peaks of the drug in the mesalazine hollow rectal suppository shell and the cannabidiol hollow rectal suppository shell were weakened, as shown in Figure 3, which indicated that the drug had certain interactions with other components in the hollow rectal suppository. The X-ray diffraction pattern shows that the diffraction peaks characteristic of the drug crystal form in the mesalazine hollow rectal suppository shell and the cannabidiol hollow rectal suppository shell disappear, as shown in Figure 4, indicating that the drug may exist in an amorphous state in the hollow rectal suppository . The thermogravimetric curves showed that all the samples had no obvious weight loss before 200°C, as shown in Figure 5. Therefore, the temperature applied during the preparation has no effect on both the drug and the material. Scanning electron microscope results (Figure 6) showed that drug crystals were visible on the surface and cross-section of the hollow rectal plug. The surface is smooth and complete, and there are holes in the cross section, and the F-MHS cracks are obvious, and the number of holes is large.

Experimental Example 2. Drug Release of Mesalazine Hollow Rectal Suppository

Materials: mesalazine hollow rectal suppository prepared according to Example 1 and Example 2, including M-MHS and F-MHS.

Methods: Two mesalazine hollow rectal suppositories, M-MHS and F-MHS, were put into dialysis bags respectively, both ends of the dialysis bags were sealed with clips, and one end was fixed on the lifting rod of the disintegration apparatus to ensure The dialysis bag can be completely immersed in the artificial intestinal fluid at 37°C, and the dialysis bag can be moved up and down at a speed of 40r/min, at 0, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, Samples were taken at 11 and 12 hours, 5 mL each time, immediately supplemented with an equal volume of artificial intestinal fluid, the samples were filtered through a 0.45 μm filter membrane, and the absorbance of the filtrate at 331 nm was measured with a UV-Vis spectrophotometer. For each mesalazine hollow rectal suppository, 3 rectal suppositories were used for dissolution testing. When the filtrate is measured, it is compared with the standard solution of mesalazine, the amount of mesalazine in the eluate is calculated, and the release curve of mesalazine in the mesalazine hollow rectal suppository is drawn.

Results: The in vitro release curves of the two mesalazine hollow rectal suppositories are shown in Figure 7. It shows that the two kinds of mesalazine hollow rectal suppositories can realize the slow release of the drug, but the release curves are somewhat different. The release rate of F-MHS is faster than that of M-MHS, which is related to the pores of the former capsule. In the future, the appropriate mesalazine hollow rectal suppository prescription and process can be selected according to the needs of drug treatment.

Experimental Example 3. Drug Release of Cannabidiol Hollow Rectal Suppositories

Material: cannabidiol hollow rectal suppository prepared according to Example 3, ie CHS.

Method: After SD rats were fasted for 12 hours, fresh rectal tissue was stripped after euthanasia, the mesentery and fat on the surface of the intestinal wall were separated, and the intestinal tissue was washed with normal saline until no excretion flowed out; CHS was put into the rectum In the cavity, both ends are sealed with surgical thread, then put into a centrifuge tube containing 7mL of normal saline, placed on a shaker at 120r/min at 37°C, at 0.5, 1, 2, 3, 4, 5, 6 Sampling every hour; 1 mL each time, supplemented with 1 mL of normal saline at 37°C after sampling; the sample was filtered through a 0.22 μm filter membrane, and the filtrate was determined by high-performance liquid chromatography; cannabidiol hollow rectal suppositories were tested with 3 rectal suppositories Dissolution assay. The detection conditions of high performance liquid chromatography include the use of octadecyl bonded silica gel column, the column temperature is 30 ℃, the mobile phase is methanol: water (85:15, v/v), the flow rate is 1.0mL/min, and the detection wavelength 220nm, injection volume 20μL.

Results: The permeable membrane release of cannabidiol hollow rectal suppository is shown in Figure 8. The cannabidiol in the cannabidiol hollow rectal suppository presents a zero-order release effect, and the release is complete in about 6 hours, which can meet the clinical drug delivery requirements.

Experimental example 4. Rat rectal residence time of hollow rectal suppository

Materials: Iohexol hollow rectal suppository prepared according to the steps of Example 1 (wherein mesalazine was replaced by iohexol).

Methods: The above-mentioned iohexol hollow rectal suppository was put into the rectum of SD rats, and the iohexol hollow rectal suppository was observed with a portable X-ray machine at 0, 1, 2, 3, 4, 4.5, 5 and 5.5 hours (h). status of stay. At the same time, photographs were taken of healthy rats without any manipulation as "no treatment" controls.

Results: X-ray showed that the iohexol hollow rectal suppository was a black shadow (the part inside the circle), as shown in Figure 9. With the prolongation of time, the iohexol hollow rectal suppository gradually dissolves, and the retention in the body is achieved for more than 5 hours, which proves that the drug-containing hollow rectal suppository has a significant rectal retention effect.

Experimental Example 5. Pharmacodynamics of Mesalazine Hollow Rectal Suppository in Treatment of Ulcerative Colitis

Material: mesalazine hollow rectal suppository prepared according to Example 2, namely M-MHS.

Methods: SD rats were fed with 7% dextran sodium sulfate aqueous solution for 7 consecutive days to obtain a rat model of ulcerative colitis. Set healthy group (without any treatment), model group (induced ulcerative colitis, without M-MHS), treatment group (induced ulcerative colitis, rectum into M-MHS, 1 tablet per day, continuous administration for 5 days), 5 rats in each group. The day of the first administration was regarded as the first day, and the rats in each group were sacrificed on the sixth day, and some colorectal tissues were taken, fixed in 4% paraformaldehyde solution, and stained with hematoxylin-eosin (H&E). Histopathological morphology was observed under a microscope, and the contents of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) were measured in part.

Results: The inflammatory injury of ulcerative colitis mainly occurred in the colorectal mucosa layer, including the damage of glands and goblet cells, which affected the intestinal mucosal barrier. Inflammatory cells appeared in the colonic mucosa of rats in the model group, with large involved areas, gland destruction, structural disorder, goblet cells decreased, and vacuoles appeared (Figure 10); after treatment with M-MHS, the colorectal tissue showed varying degrees Improvement, manifested as decreased inflammatory cell exudation, increased goblet cells, improved glandular atrophy, and arranged neatly (Figure 10).

The role of cytokines in the pathogenesis of ulcerative colitis has been recognized, and inhibition of inflammatory cytokines can alleviate intestinal inflammation. Among them, the excessive and sustained expression of TNF-α, IL-1β, and IL-6 can induce and amplify the inflammatory response. The level of TNF-α in the rectum tissue of rats in the treatment group was significantly lower than that of the model group (Fig. 11A, P<0.001), and the levels of cytokines IL-1β and IL-6 were significantly lower than those of the model group (Fig. 11B, P<0.05; Fig. 11C , P<0.05), and the level was similar to that of the normal group. Therefore, rectal administration of mesalazine hollow rectal suppository can effectively reduce the expression of inflammatory cytokines and promote the repair of damaged colorectal tissue.

Experimental example 6. Pharmacodynamics of cannabidiol hollow rectal suppository in the treatment of epilepsy

Materials: cannabidiol hollow rectal suppository prepared according to Example 3, namely CHS; 2 mg/mL cannabidiol suspension.

Method: Weigh the body weight of SD rats, inject 127mg/mL lithium chloride solution intraperitoneally with a dosage of 127mg/kg, 18 hours later, intraperitoneally inject 1mg/kg atropine solution, and 30 minutes later, intraperitoneally inject 30mg/kg hydrochloric acid Pilocarpine solution, until reaching the level V seizure on the Racine scale, lasted for 1 hour, and then terminated the seizure with 10% chloral hydrate. The SD rats were grouped into healthy group (without any treatment), model group (induced epilepsy, no CHS), positive drug group (induced epilepsy, intragastric administration of 0.3mL cannabidiol suspension), treatment group ( To induce epilepsy, the CHS was introduced into the rectum, 1 tablet per day for 3 consecutive days), 8 rats in each group. The day of the first administration was defined as the first day, and the rats were sacrificed on the fourth day, and the brain tissue was taken out, part of which was fixed in 4% paraformaldehyde solution, and histopathological morphology was observed under a microscope after H&E staining. A part of the determination of the content of TNF-α, IL-1β, IL-6.

Results: The rat epilepsy model induced by lithium chloride-pilocarpine hydrochloride was similar to human temporal lobe epilepsy in the brain pathological changes, and the neurons in the CA3 area of the hippocampus showed obvious changes. The neurons in the CA3 area of the hippocampus of the SD rats in the model group were arranged in disorder, lost the normal cytoskeleton structure, and the neurons were severely degenerated and missing; The neat shape was normal, and the neuron loss was effectively improved, and the improvement effect of the cannabidiol hollow rectal suppository was more obvious (Figure 12).

The pathogenesis of epilepsy is closely related to the dysfunction of the body's immune system. Cytokines are widely involved in immune regulation, among which TNF-α, IL-1β, and IL-6 are common cytokines in immune regulation. After cannabidiol treatment, the level of TNF-α in the brain tissue of SD rats was significantly lower than that of the model group (Figure 13A, P<0.05), and the levels of cytokines IL-1β and IL-6 were significantly lower than those of the model group (Figure 13B, P<0.001 ), and the treatment group was closer to the normal group level. Therefore, rectal administration of cannabidiol hollow rectal suppository can effectively promote the recovery of brain neurons, reduce the expression of inflammatory cytokines, and effectively relieve the symptoms of epilepsy.

Claims (10)

1. A drug-containing hollow rectal suppository, which is cylindrical as a whole, composed of an outer part of the plug shell containing a polymer, a porogen and a drug, and an inner part of a spring, and is hollow inside. 2. The medicated hollow rectal suppository according to claim 1, the outer part of the capsule shell is a curved capsule shell. 3. The medicated hollow rectal suppository according to claim 2, the appearance of the curvilinear capsule shell is narrow at the top and wide at the bottom. 4. The medicine-containing hollow rectal suppository according to claim 1, the preparation method of the outer part of the capsule shell is a mold perfusion method. 5. The hollow rectal suppository containing medicine according to claim 1, the preparation method of the inner part spring is a 3D printing method. 6. The drug-containing hollow rectal suppository according to claim 1, wherein the polymer is selected from the group consisting of propylene-butadiene-styrene-diene copolymer, polyvinyl alcohol, polylactic glycolic acid, polycaprolactone, thermoplastic polyurethane, photosensitive resin. 7. The medicated hollow rectal suppository according to claim 1, wherein the porogen is selected from sucrose, lactose, glucose, propylene glycol, glycerin, polyethylene glycol, and sodium chloride. 8. The hollow rectal suppository containing medicine according to claim 1, wherein the medicine for treating ulcerative colitis and the medicine for treating epilepsy. 9. The drug-containing hollow rectal suppository according to claim 1 is a mesalazine hollow rectal suppository prepared by the following steps: preparing the mesalazine hollow rectal suppository shell by mold perfusion: weighing 2g of polyvinyl alcohol, adding 3mL of water and 2mL of glycerin were heated in a water bath and stirred continuously to obtain a paste mixture of polyvinyl alcohol. In addition, 0.08g of polyethylene glycol 1000, 0.32g of polyethylene glycol 8000, and 0.32g of mesalamine were respectively taken, and the above polyvinyl alcohol was added In the pasty mixture, stir well and evenly to obtain the mesalamine pasty mixture; the mesalamine hollow rectal suppository mold is composed of three parts, two 4 die structures except the lock structure are used to form the mesalamine hollow The external part of the rectal suppository is a cuboid in shape, 70 mm long, 17 mm wide, and 6 mm thick. The concave part is composed of two incomplete symmetrical spherical spaces, the narrowest and widest from top to bottom There are 5 locations, the distances of which are 7 mm, 9.2 mm, 8.5 mm, 11.2 mm, and 6.6 mm, and a 4-cylindrical structure used to form the hollow structure inside the mesalazine hollow rectal suppository. Its bottom is a cuboid with a length of 70 mm, width 16 mm, thickness 2 mm, cylindrical structure diameter 6.5 mm, height 17 mm, spacing 7.4 mm; pour the mesalamine paste mixture into the mesalamine hollow rectal suppository mold, and let stand at minus 20 ° C for 2 hours As mentioned above, the curved mesalazine hollow rectal suppository shell was obtained by demoulding; the internal spring of the mesalazine hollow rectal suppository was prepared by 3D printing: the internal spring structure was designed through 3D design software modeling, and the wire diameter was 0.85mm. The ring diameter is 5.60 mm, the pitch is 0.88 mm, converted into a 3D printer-recognizable parameter file, and the thermoplastic polyurethane extruded wire is loaded into the fused deposition 3D printer. The printing parameters include nozzle temperature 200°C, hot bed temperature 30°C, and printing speed 70mm/s , the spring embryo is prepared, and the connecting part between the spring wires is divided with a knife to obtain the inner part of the spring; the assembly of the mesalazine hollow rectal suppository: the mesalazine hollow rectal suppository shell and the mesalazine hollow rectal suppository Part of the spring is compressed laterally, and one end is inserted into the opening of the mesalazine hollow rectal plug shell, one end of the plug shell is blocked, and the spring is continuously rotated until the spring is completely inserted into the outer part of the plug shell to obtain the mesalazine hollow rectal plug. 10. The drug-containing hollow rectal suppository according to claim 1 is a mesalazine hollow rectal suppository prepared by the following steps: preparing the mesalazine hollow rectal suppository shell by fused deposition 3D printing method: weighing 1 g polyethylene glycol Alcohol 1000, heated in a water bath at 37°C, add 1g of mesalazine and 8g of polyvinyl alcohol, stir evenly, dry at 50°C for 3 hours, leave it at room temperature, make small blocks, put them into the trough of the extruder, and extrude Finally, a mesalazine extruded wire with a diameter of about 1.75 mm was obtained; through 3D design software modeling, the outer shell structure was designed as a curved shell structure, which was composed of a hollow cylinder with a diameter of 7 mm and a curved shell inside. There are 5 narrowest and widest positions of the curved shell from top to bottom, and the distances are 7mm, 9.4mm, 9mm, 10mm, and 7mm respectively. Convert it into a 3D printer-recognizable parameter file and select the appropriate parameter for printing , to obtain a curved mesalazine hollow rectal suppository shell; use 3D printing to prepare the internal spring of the mesalazine hollow rectal suppository: use 3D design software to model and design the internal spring structure, with a wire diameter of 0.85 mm and a coil diameter of 5.60 mm. mm, pitch 0.88 mm, converted into a 3D printer recognizable parameter file, and the thermoplastic polyurethane extruded wire was loaded into the fused deposition 3D printer. The printing parameters included nozzle temperature 200°C, hot bed temperature 30°C, printing speed 70mm/s, and prepared Spring embryo, use a cutter to divide the connecting part between the spring wires to get the inner part of the spring; the assembly of the mesalazine hollow rectal suppository: put the mesalazine hollow rectal suppository shell and the mesalazine hollow rectal suppository internal part of the spring horizontally Compress, insert one end into the opening of the mesalazine hollow rectal plug shell, block one end of the plug shell, and continuously rotate the spring to insert it until the spring is completely inserted into the outer part of the plug shell to obtain the mesalazine hollow rectal suppository.