Ibuprofen suppositories, process for their preparation and use

Abstract

The application provides a ibuprofen suppository, a preparation method and application thereof, and belongs to the technical field of medicines. The application overcomes the defects of slow effect, easy leakage and low bioavailability of traditional suppositories. The suppository is a hollow suppository, which comprises a shell layer and content filled in a hollow cavity of the shell layer; the shell layer is composed of a water-soluble base and a bioadhesive material, the water-soluble base is a mixture of PEG 400 and PEG 1000 ; the content contains ibuprofen active ingredients and an absorption promoter; the content is in the form of a solid powder, when the suppository enters the rectum, the shell layer dissolves and adheres to the rectal mucosa, and the content is directly exposed to the rectal body fluid in the form of a solid powder and is quickly dissolved. The application is particularly suitable for children's antipyretic and analgesic drug preparation, and has the advantages of rapid effect, accurate dosage and good compliance.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to an ibuprofen suppository, its preparation method, and its application. Background Technology

[0002] Ibuprofen (chemical name: 2-(4-isobutylphenyl)propionic acid), a classic nonsteroidal anti-inflammatory drug, has become a cornerstone drug for the management of fever and pain in children worldwide since its introduction in 1969 due to its excellent antipyretic efficacy and good safety profile. It has also received joint recommendations from the World Health Organization and the U.S. Food and Drug Administration.

[0003] However, current mainstream pediatric formulations face significant challenges in clinical application. While oral suspensions facilitate dosage adjustment, their practicality is low for infants and young children experiencing vomiting or resistance to medication, and they cannot avoid direct gastrointestinal irritation. Widely used suppositories (usually made by melting the drug into a fatty matrix such as semi-synthetic fatty acid esters and then molding it), although bypassing the first-pass effect, have a series of technical defects that urgently need to be addressed: First, their onset speed cannot meet the needs of emergency cases. The drug must undergo matrix melting and dissolution and diffusion in rectal fluid before it can be absorbed, resulting in slow in vitro dissolution (only about 72% dissolution rate at 60 minutes for commercially available products), and a peak time to absorption (Tmax) that is generally long, ranging from 60 to 90 minutes. This delays fever reduction in children with high fever, prolongs suffering, and increases the risk of complications. Second, the accuracy of dosage is difficult to guarantee. After the suppository melts in the rectum, its contents are prone to leakage or movement into deeper tissues due to intestinal peristalsis, especially in children with shorter rectums and more active peristalsis, leading to unstable actual absorption, affecting efficacy and posing potential safety risks. Furthermore, poor patient compliance and the hard texture of traditional fatty matrix suppositories, coupled with oily residue after use, significantly increase the foreign body sensation and nursing burden during administration. Finally, the drug is dispersed in a microcrystalline form within the fatty matrix, and long-term storage may lead to crystal transformation or migration, affecting the uniformity of product content and the stability of dissolution behavior. Although some studies have attempted to add bioadhesive materials such as carbomer to ordinary suppositories, these have mostly been simple additions, failing to systematically realize their technological potential.

[0004] To overcome the aforementioned limitations, hollow suppositories have emerged as an innovative dosage form. They physically separate the outer shell matrix from the drug within the hollow cavity, offering advantages such as avoiding drug-matrix interactions, flexibly controlling drug release behavior, and achieving personalized dosage filling. However, current research on hollow suppositories largely remains at the general conceptual level, lacking systematic formulation development and process optimization for the specific drug ibuprofen, and failing to address the crucial issue of deeply integrating "hollow structure" with "bioadhesion technology." Specifically, designing a suppository that maintains good formability while achieving rapid drug release and prolonging the formulation's residence time at the absorption site remains a mature and reliable technical solution. Therefore, based on an in-depth analysis of the shortcomings of existing technologies, developing a novel ibuprofen suppository for children that integrates rapid onset of action, high bioavailability, good patient compliance, accurate dosage, and simple manufacturing process has clear clinical necessity and significant industrial value. Summary of the Invention

[0005] In view of this, the present invention aims to solve at least one or more technical problems existing in the prior art. Specifically, the purpose of the present invention is to provide an ibuprofen suppository and its preparation method to overcome the following technical defects of existing ibuprofen suppositories (especially pediatric suppositories): Slow onset of action: After administration of existing ordinary suppositories (such as fatty matrix suppositories), the drug needs to undergo multiple steps such as matrix melting, drug release, dissolution or dispersion in rectal fluid, and finally absorption through the mucosa. In vitro dissolution studies have shown that the dissolution rate of commercially available pediatric ibuprofen suppositories is only about 72% at 60 minutes and still less than 82% at 90 minutes, resulting in a long clinical onset time (Tmax is usually 60-90 minutes), which cannot meet the clinical needs of rapid fever reduction in children with high fever. Limited bioavailability: After ordinary suppositories melt in the rectum, the melt is easily affected by intestinal peristalsis and moves towards the terminal colon or even flows out of the anus, resulting in a shortened contact time and reduced contact area between the drug and the rectal mucosa, causing inaccurate dosage and incomplete drug absorption, thereby limiting its bioavailability. Poor compliance in children: Traditional suppositories are mostly made of a single fatty base, which is relatively hard and causes a strong foreign body sensation when inserted, easily leading to crying and resistance from children; after melting, the oil overflows, easily staining clothing and causing inconvenience for parents. Stability issues: Ibuprofen is a poorly soluble drug. In ordinary suppositories, the drug is dispersed in the base in the form of microcrystals. Long-term storage may pose a risk of crystal transformation or drug migration, affecting the uniformity of content and dissolution behavior.

[0006] In order to solve the above-mentioned technical problems and achieve the above-mentioned objectives of the present invention, the present invention adopts the following technical solution: An ibuprofen suppository, the suppository being a hollow suppository, comprising an outer shell and contents filled within a hollow cavity of the outer shell; The outer shell is composed of a water-soluble matrix and a bioadhesive material; The contents contain ibuprofen active ingredient and absorption enhancer; In the above technical solution, the physical separation of the drug is achieved through a "hollow structure": the outer shell undertakes the functions of shaping and adhesion, while the contents are responsible for rapid drug release. When the suppository is inserted into the rectum, the water-soluble outer shell quickly dissolves or melts, releasing the contents powder. The powder directly contacts the rectal mucosa and is rapidly dissolved and absorbed, thus avoiding the rate-limiting step in traditional suppositories where the drug must first be released from the matrix.

[0007] Preferably, the water-soluble matrix is ​​selected from one or a mixture of several of polyethylene glycol (PEG), poloxamer, and polyoxyethylene monostearate. More preferably, the water-soluble matrix is ​​polyethylene glycol 400 (PEG). 400 ) and polyethylene glycol 1000 (PEG) 1000 A mixture of PEG and PEG. Experiments show that PEG alone is difficult to simultaneously meet the requirements of good moldability and rapid melt transfer, while PEG... 400 With PEG 1000 The combination of these factors can synergistically regulate the melting point and melting time of the suppository.

[0008] More preferably, the PEG 400 With PEG 1000 The mass ratio is (20-30):(80-70). Within this range, the suppository shell maintains sufficient hardness at room temperature (for easy storage and use) while melting rapidly at rectal temperature (37°C) (melting time less than 20 minutes). Particularly preferred is a mass ratio of 25:75, at which point the suppository's formability and rapid release properties are optimally balanced.

[0009] Preferably, the bioadhesive material is selected from one or more of carbomer, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, and polycarbofil. More preferably, the bioadhesive material is carbomer (such as carbomer 934P, 940, 971P, etc.). Carbomer rapidly hydrates upon contact with water to form a viscous gel, which allows the suppository shell to adhere to the surface of the rectal mucosa, significantly prolonging the retention time of the preparation at the absorption site and preventing the leakage of the drug solution or contents.

[0010] More preferably, the amount of carbomer used accounts for 1% to 2.0% of the total weight of the outer shell layer. Experiments have shown that when the amount of carbomer is less than 0.5%, the improvement in adhesion is not significant; when the amount is greater than 2.0%, the viscosity of the molten matrix increases significantly, leading to difficulties in casting and potentially delaying the melting rate of the outer shell. Particularly preferably, the amount of carbomer used is 1.0% to 1.5%, at which point the adhesion can reach 18 to 21 g / cm³. 2 It increased by about 8 to 10 times compared to the control group without carbomer, without affecting the melting behavior of the shell.

[0011] Preferably, the absorption enhancer is selected from one or more of poloxamer, Tween-80, sodium lauryl sulfate, and polyoxyethylene hydrogenated castor oil. More preferably, the absorption enhancer is poloxamer 188. Poloxamer 188 is a nonionic surfactant that not only increases the wettability and solubility of ibuprofen, but may also promote transmembrane absorption of the drug by affecting cell membrane fluidity.

[0012] More preferably, the mass ratio of ibuprofen to absorption enhancer in the contents is 1:(0.02-0.1). Within this range, the absorption enhancer effectively improves the dissolution rate of ibuprofen without causing mucosal irritation due to excessive dosage. In vitro dissolution experiments show that when the mass ratio of ibuprofen to poloxamer 188 is 1:0.05, the dissolution rate can reach over 98% after 20 minutes, significantly better than the control group without added enhancer (dissolution rate of only 68.5% after 20 minutes).

[0013] In a preferred embodiment of the invention, to further improve the solubility and chemical stability of ibuprofen, the contents further include hydroxypropyl-β-cyclodextrin. Ibuprofen forms an inclusion complex with hydroxypropyl-β-cyclodextrin, which can encapsulate the hydrophobic ibuprofen molecule within the hydrophilic cavity of the cyclodextrin, thereby significantly improving the apparent solubility and dissolution rate of the drug.

[0014] Preferably, the molar ratio of ibuprofen to hydroxypropyl-β-cyclodextrin is 1:(1-2). Experiments have shown that when the molar ratio is 1:1.5, the inclusion rate can reach over 92%, and the solubility of ibuprofen in the inclusion compound is approximately 20 times higher than that of the raw drug. This inclusion compound not only improves the dissolution behavior of ibuprofen but also masks the unpleasant bitter taste of the drug, improving patient compliance.

[0015] In one specific embodiment of the present invention, each suppository contains 50 mg or 100 mg of ibuprofen, which is suitable for children of different ages (e.g., 6 months to 3 years, or 3 years and older).

[0016] To achieve the objective of this invention, another technical solution is adopted: a method for preparing the ibuprofen suppository, comprising the following steps: (1) Shell preparation: The water-soluble matrix is ​​heated and melted, the bioadhesive material is added and stirred evenly, and then poured into the suppository mold while hot. The shaping component is inserted, and after cooling and solidification, the shaping component is pulled out to form a suppository shell with a hollow cavity. (2) Content preparation: Ibuprofen active ingredient and absorption promoter are mixed evenly, and hydroxypropyl-β-cyclodextrin is optionally added for inclusion treatment to obtain a solid powder content mixture; (3) Filling and sealing: Fill the hollow cavity obtained in step (1) with the mixture of contents obtained in step (2) in the form of solid powder, then seal with molten matrix, cool and demold to obtain the product.

[0017] Preferably, the water-soluble matrix in step (1) is PEG. 400 and PEG 1000 The mixture is heated to 65–75°C, and the shaping component is a metal or plastic rod with a diameter of 2–4 mm. The insertion depth is 1.5–2.5 cm from the end of the plug. By adjusting the insertion depth, the cavity volume and drug release rate can be controlled.

[0018] Preferably, the mixing method in step (2) is grinding or air-jet milling, so that the particle size D of the mixture is... 90 Less than 20 μm. Micronization increases the specific surface area of ​​the drug, further promoting rapid dissolution.

[0019] Preferably, when step (2) includes hydroxypropyl-β-cyclodextrin, the ibuprofen-hydroxypropyl-β-cyclodextrin inclusion complex is prepared by a grinding method or a solvent method. The grinding method involves grinding ibuprofen, hydroxypropyl-β-cyclodextrin, and a small amount of solvent (such as water or ethanol) together until a uniform paste is formed, which is then dried and pulverized. This method is simple, rapid, does not use organic solvents, and is suitable for industrial production.

[0020] A third aspect of the present invention provides the use of the above-described ibuprofen suppositories or ibuprofen suppositories prepared by the above-described preparation method in the preparation of a medicament for treating fever or pain in children.

[0021] Preferably, the fever in the child is an acute high fever caused by a cold or influenza; the pain in the child is mild to moderate, including but not limited to teething pain, earache, headache, post-vaccination pain, etc.

[0022] Preferably, the application involves adjusting the dosage according to the child's weight, with a recommended dose of 5-10 mg / kg per dose, every 6-8 hours, not exceeding 4 times within 24 hours.

[0023] Compared with the prior art, the present invention achieves the following technical effects: 1) Significant immediate-release characteristics: Through the synergistic design of "hollow structure + immediate-release contents," the rate-limiting step of slow drug release from the matrix in traditional suppositories is avoided. In vitro dissolution tests show that the suppositories of this invention achieve a dissolution rate of over 45% at 5 minutes, nearly 80% at 10 minutes, and a cumulative dissolution rate exceeding 97% within 20 minutes. In contrast, commercially available ordinary pediatric ibuprofen suppositories have a dissolution rate of only 29.5% at 20 minutes and still less than 75% at 60 minutes. This indicates that the drug release rate of the suppositories of this invention is 3 to 4 times faster than existing products, meeting the clinical need for rapid fever reduction in children with high fever.

[0024] 2) Significantly Improved Bioavailability: This invention improves bioavailability through two levels of innovation: First, the carbomer in the outer shell enables the suppository to exhibit strong bioadhesion in the rectum (adhesion force reaches 18-21 g / cm², 8-10 times higher than ordinary suppositories), effectively prolonging the retention time of the formulation at the absorption site; second, the absorption enhancer (poloxamer 188) in the contents improves the wetting and penetration of the drug on the mucosal surface. The synergistic effect of these two factors is expected to increase the relative bioavailability in vivo by 30%-50% compared to ordinary suppositories (based on pharmacokinetic theory).

[0025] 3) Superior child compliance: Utilizing a water-soluble PEG matrix, it is non-greasy upon insertion and easy to clean after melting; the addition of carbomer creates a soft gel with minimal irritation to the rectal mucosa. Furthermore, cyclodextrin inclusion technology effectively masks the bitter taste of ibuprofen, further improving child acceptance.

[0026] 4) Flexible dosage adjustment capability: The hollow structure allows for precise filling of different dosages of drugs according to clinical needs. It can produce fixed specifications (such as 50mg / capsule, 100mg / capsule) or realize personalized pediatric dosing (such as customized dosage according to weight), which solves the clinical problem of fixed dosage and inconvenient adjustment of traditional suppositories.

[0027] 5) Excellent stability: The contents are in solid powder form, avoiding potential leakage and drug migration issues associated with liquid contents. When cyclodextrin inclusion complexes are used, ibuprofen is encapsulated within the cyclodextrin cavity, effectively preventing degradation caused by light, heat, and oxygen. Long-term stability tests show that after 24 months of storage at 25°C, there are no significant changes in product properties, content, or dissolution behavior, demonstrating the product's excellent shelf-life stability.

[0028] 6) Simple preparation process: The preparation method of this invention has a simple process route, requires no complex equipment, and the main unit operations include melting, mixing, and filling, making it suitable for large-scale industrial production. In particular, the grinding method for preparing cyclodextrin inclusion complexes does not use organic solvents, making it environmentally friendly and safe, in line with the concept of green pharmaceuticals.

[0029] In summary, this invention, through the organic combination of three major technical features—hollow structure, bioadhesive shell, and immediate-release contents—has successfully developed an ibuprofen suppository that is rapidly effective, completely absorbed, has good compliance, flexible dosage, and stable quality. It is particularly suitable for pediatric clinical applications and has significant technological advancements and practical value. Attached Figure Description

[0030] For ease of explanation, the present invention will be described in detail below with reference to specific embodiments and accompanying drawings.

[0031] Figure 1 This is a flowchart of the ibuprofen suppository preparation method of the present invention. Detailed Implementation

[0032] The following are specific embodiments of the present invention, described in conjunction with the accompanying drawings, to further illustrate the technical solutions of the present invention. However, the present invention is not limited to these embodiments. Specific details, such as particular configurations, are provided in the following description merely to aid in a comprehensive understanding of the embodiments of the present invention. Therefore, those skilled in the art should understand that various changes and modifications can be made to the embodiments described herein without departing from the scope and spirit of the present invention.

[0033] It should be noted that, unless otherwise specified, the embodiments and features described in this invention can be combined with each other.

[0034] Example 1: Screening of Suppository Shell Matrix 1) Experimental objective: To screen shell matrix combinations that can balance room temperature hardness, rapid melting at body temperature, and good bioadhesion.

[0035] 2) Experimental methods: (a) Matrix composition: PEG 400 PEG 600 With PEG respectively 1000 The mixtures were prepared in different mass ratios (20:80, 25:75, 30:70, 40:60), and control groups without carbomer and experimental groups containing different proportions of carbomer (0.5%, 1.0%, 1.5%, 2.0%) were set up.

[0036] (b) Preparation of blank plugs: Weigh 100g of each formulation matrix and place it in an evaporating dish. Heat in a water bath at 70-75℃ until melted. Stop heating when 2 / 3 of the matrix has melted and stir with residual heat until completely dissolved. After slightly cooling, pour into a plug mold coated with lubricant. Cool for 30 minutes, scrape off the overflow, and demold to obtain the blank plug.

[0037] (c) Evaluation indicators: ① Melting time limit: According to the "Melt-time Limit Test Method" of the General Chapter of Part IV of the 2020 Chinese Pharmacopoeia, take 3 samples and determine the time for complete melting at 37℃.

[0038] ② Appearance and hardness: Observe the appearance of the suppository (whether there are cracks, dents, and color uniformity); use a texture evaluation instrument to measure the hardness (probe diameter 2mm, test speed 1mm / s, puncture depth 5mm).

[0039] ③ Adhesion force determination: Following the method described in the literature, a fresh isolated rat colon segment was taken and fixed to a stainless steel plate. The molten matrix was evenly coated onto another steel plate, and 100g of pressure was applied between the two plates. The plate was preheated at 37℃ for 5 minutes, and then water was added to a plastic bag at a rate of 2ml / min until separation. The adhesion force (g / cm²) was calculated. 2 ).

[0040] 3) Experimental results: see Table 1 below.

[0041] Table 1 Comparison of physical properties of different matrix formulations

[0042] 4) Experimental conclusion: PEG 400 / PEG 1000 (25:75) Combination (Formula A2) compared to PEG 600 The combination exhibits a shorter melt transition time (19.3 min vs 43.6 min), making it more suitable for immediate-release formulations. The addition of carbomer (formulas C2, C3, and C4) slightly shortens the melt transition time (possibly due to carbomer's water absorption promoting matrix dispersion), while maintaining relatively stable hardness, but significantly improves adhesion (from approximately 2.3 g / cm² to 18.7–23.5 g / cm²). Considering both adhesion performance and filling operability, PEG was selected. 400 :PEG 1000 =25:75, with a carbomer content of 1.0% to 1.5% as the preferred formulation for the outer shell.

[0043] Example 2: Screening of absorption enhancers 1) Experimental objective: To screen for absorption promoters that can maximize the in vitro dissolution rate of ibuprofen.

[0044] 2) Experimental methods: Following the basic formulation of Example 1, poloxamer 188 in the contents was replaced with equal amounts of Tween-80 and sodium dodecyl sulfate (SDS), or no accelerator was added (control group). In vitro dissolution tests were performed on the contents powders of different formulations. An appropriate amount of powder (equivalent to 50 mg of ibuprofen) was added to 900 ml of pH 7.2 phosphate buffer. The mixture was subjected to a slurry method at 50 rpm and 37℃ ± 0.5℃. Samples were taken at 5, 10, 15, 20, and 30 min to determine the concentration and calculate the cumulative dissolution rate.

[0045] 3) Experimental results: see Table 2 below.

[0046] Table 2. Effects of different absorption enhancers on the dissolution of ibuprofen powder (n=6)

[0047] 4) Experimental Conclusion: All three surfactants significantly improved the dissolution rate of ibuprofen, with poloxamer 188 showing the best effect, achieving a dissolution rate of 98.5% after 20 minutes. Poloxamer 188 not only has a solubilizing effect but may also promote rapid drug dispersion by inhibiting drug recrystallization and increasing wettability. Therefore, poloxamer 188 is the preferred absorbance enhancer for the contents.

[0048] Example 3: Preparation of ibuprofen hollow suppositories with basic formulation (containing carbomer) 1) Prescription (based on 1000 tablets, each containing 50mg ibuprofen): Outer shell: PEG 400 250g, PEG 1000 750g, Carbomer 940 10g (i.e. 1.0%).

[0049] Contents: 50g ibuprofen raw material, 2.5g poloxamer 188.

[0050] 2) Preparation process: (a) Shell preparation: Take the prescribed amount of PEG 400 and PEG 1000 Place the mixture in a stainless steel jacketed kettle and heat it in a water bath to 70–75°C, stirring until completely melted. Slowly sprinkle Carbomer 940 fine powder (passed through a 100-mesh sieve) into the molten matrix while stirring continuously until a uniform, lump-free viscous liquid is formed. Maintain the temperature at 65–70°C and pour the hot mixture into a stud mold coated with a release agent (liquid paraffin). Quickly insert a 3mm diameter, spherical-tipped shaping rod vertically into the center of each hole (insertion depth 2.0cm from the stud tail), and allow it to cool naturally for 30–40 minutes. After complete solidification, carefully rotate and pull out the shaping rod to obtain a stud shell with a hollow cavity. Check that the cavity is intact and free of cracks.

[0051] (b) Contents preparation: Ibuprofen raw material and poloxamer 188 were mixed according to the prescription amount and micronized in an air jet mill to achieve a particle size D 90 For particles smaller than 20 μm, grind and mix thoroughly in a ball mill for 1 hour, then pass through a 100-mesh sieve to obtain a uniform mixed powder.

[0052] (c) Filling and Sealing: Using a micro-powder filling machine, the above-mentioned mixed powder is precisely filled into the hollow cavity, with each cavity containing the equivalent of 50 mg of ibuprofen. Immediately after filling, a small amount (approximately 0.2 g / capsule) of preheated and molten PEG is applied. 400 / PEG 1000 The mixed matrix (excluding carbomer) is dripped into the end of the mold. It is then placed on a cooling plate to cure for 20 minutes. The excess material overflowing from the mold opening is scraped off, and the mold is removed. Those with incomplete shapes are discarded to obtain the finished product.

[0053] (d) Packaging: Seal qualified suppositories in aluminum-plastic composite film bags and store them in a dry place below 25°C.

[0054] Example 4: Preparation of ibuprofen hollow suppositories containing cyclodextrin (to improve stability) 1) Prescription (based on 1000 tablets): Outer shell: Same as in Example 1.

[0055] Contents: Ibuprofen 50g, Hydroxypropyl-β-cyclodextrin (HP-β-CD) 145g, Poloxamer 188 2.5g.

[0056] 2) Preparation process: (1) Preparation of ibuprofen-HP-β-CD inclusion complex: The grinding method was used. HP-β-CD was placed in a mortar, and an appropriate amount of water (about 1.5 times the weight of HP-β-CD) was added and ground until a paste was formed. Ibuprofen was dissolved in a small amount of anhydrous ethanol and added to the above paste. The mixture was ground thoroughly for 2 hours until a uniform paste was formed. The paste was then dried in a vacuum drying oven at 40℃ for 24 hours. After drying, the paste was pulverized and passed through a 100-mesh sieve to obtain the inclusion complex powder.

[0057] (2) Content determination: The content of ibuprofen in the inclusion complex was determined by UV method, and the inclusion rate was calculated. The results showed that the inclusion rate could reach more than 92%.

[0058] (3) Mixing of contents: Mix the above inclusion compound powder with poloxamer 188 evenly.

[0059] (4) Subsequent steps: Same as steps (1), (3), and (4) in Example 1.

[0060] Example 5: Preparation of Ibuprofen Hollow Suppositories with Adjusted Drug Release Rate This embodiment adjusts the initial drug release rate by changing the cavity depth (i.e., the drug filling position). The preparation method is the same as in Example 3, except that the insertion depth of the shaping rod is different.

[0061] Hollow plug-A (quick-release type): The shaping rod is inserted to a depth of 1.5cm (the cavity is shallow, closer to the plug tail outlet).

[0062] Hollow suppository-B (Sustained-release type): The insertion depth of the shaping rod is 2.5cm (the cavity is deep, and the drug is more tightly wrapped by the outer shell).

[0063] Experimental Example 1: Establishment of Content Determination Methodology 1) Selection of detection wavelength: An appropriate amount of ibuprofen reference standard was dissolved in 50% ethanol and scanned within the wavelength range of 200–400 nm. The results showed that ibuprofen had absorption peaks at 222 nm and 263 nm. Considering the terminal absorption interference of the excipient PEG near 222 nm, 263 nm was selected as the detection wavelength. Verification showed that the blank excipient had no absorption at 263 nm.

[0064] 2) Preparation of Standard Curve: Accurately weigh 20 mg of ibuprofen reference standard, place it in a 100 ml volumetric flask, dissolve and dilute to the mark with 50% ethanol, and shake well to obtain a stock solution of 200 μg / ml. Accurately measure an appropriate amount of the stock solution to prepare a series of standard solutions with concentrations of 5, 10, 20, 30, 40, and 50 μg / ml. Using 50% ethanol as a blank, the absorbance (A) was measured at a wavelength of 263 nm. Linear regression was performed on the absorbance (A) against the concentration (C) to obtain the standard curve equation: A = 0.0326C + 0.0087 (r = 0.9998, n=6). The results show that ibuprofen has a good linear relationship in the concentration range of 5–50 μg / ml.

[0065] 3) Precision and recovery rate: Precision: Three quality control samples with low, medium, and high concentrations (10, 25, and 40 μg / ml) were prepared and measured five times within the same day. The intra-day RSDs were 1.2%, 0.9%, and 1.1%, respectively. After three consecutive days of measurement, the inter-day RSDs were 1.8%, 1.5%, and 1.7%, respectively. This indicates that the method has good precision.

[0066] Recovery rate: Blank excipients equivalent to 8 mg, 10 mg, and 12 mg of ibuprofen were accurately weighed, and 8 mg, 10 mg, and 12 mg of ibuprofen reference standard were accurately added respectively. The solutions were prepared according to the test solution preparation method and then analyzed. The average recoveries were 99.2%, 100.3%, and 99.8%, respectively, with RSDs all less than 2.0% (n=9), indicating high accuracy of the method.

[0067] Experiment Example 2: Quality Inspection of Three Batches of Samples Three batches of samples prepared in Example 1 (batch numbers: 20240601, 20240602, 20240603) were subjected to full testing according to the requirements of the suppository section of the 2020 edition of the Chinese Pharmacopoeia. The results are shown in Table 3 below.

[0068] Table 3. Quality Inspection Results of Three Batches of Ibuprofen Hollow Caps

[0069] Experimental Example 3: Comparative Study of In Vitro Dissolution 1) Experimental Methods: Samples prepared in Example 3 (basic formulation) and Example 4 (cyclodextrin inclusion complex), as well as commercially available brand of children's ibuprofen suppositories (fatty matrix, 50 mg / suppository), were used for dissolution determination according to Method II (slurry method) of the 2020 edition of the Chinese Pharmacopoeia. The dissolution medium was pH 7.2 phosphate buffer (containing 0.02% poloxamer 188), 900 ml in volume, at a temperature of 37℃±0.5℃ and a rotation speed of 50 r / min. 5 ml samples were taken at 5, 10, 15, 20, 30, 45, 60, and 90 min (with simultaneous replenishment of the same volume of medium at the same temperature), filtered, and the absorbance of the filtrate was measured at 263 nm. The cumulative dissolution percentage was calculated.

[0070] 2) Experimental results: See Table 4 below. Table 4. Comparison of cumulative in vitro dissolution rates of different ibuprofen suppositories (%, n=6)

[0071] 3) Experimental Conclusions: Commercially available suppositories dissolve slowly, with a dissolution rate of only 81.5% after 90 minutes. In contrast, the hollow suppositories prepared in this invention (Examples 3 and 4) exhibited a dissolution rate exceeding 97% within 20 minutes, demonstrating significant rapid-release characteristics. Example 3 was slightly faster than Example 4, possibly because ibuprofen exists in free form, resulting in faster release. Example 4, due to cyclodextrin inclusion, showed a slight delay in dissolution but still achieved complete release within 20 minutes, and the cyclodextrin inclusion helps improve drug stability.

[0072] Experiment Example 4: Pharmacodynamic Study – Antipyretic Experiment in Yeast-Induced Fever Rats 1) Experimental objective: To evaluate the antipyretic effect of the ibuprofen hollow suppository of the present invention on the fever model.

[0073] 2) Experimental Methods: Sixty SD rats, weighing 180–220 g, were randomly divided into 6 groups of 10 rats each: ① Normal control group (no drug administration, no modeling); ② Model control group (no drug administration, only modeling); ③ Commercially available suppository group; ④ Low-dose group of Example 1 of this invention (25 mg / kg); ⑤ High-dose group of Example 3 of this invention (50 mg / kg); ⑥ Group 4 of this invention (50 mg / kg). Except for the normal control group, the rats in the other groups were subcutaneously injected with 10 ml / kg of 20% dry yeast suspension in the back to induce fever. Five hours after fever induction (body temperature rise of at least 1.0 °C), the corresponding drugs were administered rectally to each group. Rectal temperature was measured at 0.5 h, 1 h, 2 h, 3 h, 4 h, and 6 h after drug administration, and the temperature change value (ΔT) was calculated.

[0074] 3) Experimental results: see Table 5 below.

[0075] Table 5. Changes in body temperature (ΔT, ℃, n=10) at different time points after drug administration in each group of rats.

[0076] Note: * P < 0.05 compared with the model control group; # P < 0.05 compared with the commercially available suppository group.

[0077] 4) Conclusion: Both Examples 3 and 4 of this invention can significantly reduce the body temperature of febrile rats, and the onset of action is rapid. A significant cooling effect is observed 0.5 hours after administration, reaching its peak at 1-2 hours, with the effect intensity showing a dose-dependent relationship. At the same dose (50 mg / kg), the cooling effect of Examples 3 and 4 of this invention at 0.5 hours and 1 hour after administration is significantly better than that of commercially available ordinary suppositories (P<0.05), demonstrating the advantage of the rapid-release characteristics of the hollow suppositories in this invention.

[0078] Experimental Example 5: Long-term stability test Three batches of samples from Example 3 were taken and, according to their market packaging, placed at a temperature of 25℃±2℃ and a relative humidity of 60%±10%. Samples were taken at 0, 3, 6, 9, 12, 18, and 24 months to investigate their properties, content, melting time, related substances, and microbial limits. The results are shown in Table 6 below (taking batch number 20240601 as an example).

[0079] Table 6. Long-term stability test results of ibuprofen hollow plugs (25℃±2℃, RH60%±10%)

[0080] Conclusion: During the 24-month long-term observation period, there were no significant changes in any of the quality indicators of this product, indicating good stability. The tentative shelf life is 24 months.

[0081] Those skilled in the art to which this application pertains may modify or supplement the specific embodiments described or use similar methods to replace them, but without departing from the inventive concept of this application or exceeding the scope defined by the appended claims.

Claims

1. An ibuprofen suppository, characterized in that, The suppository is a hollow suppository, comprising an outer shell and contents filled within the hollow cavity of the outer shell; The outer shell is composed of a water-soluble matrix and a bioadhesive material; The contents contain ibuprofen active ingredient and absorption enhancer; The contents are in the form of a solid powder. When the suppository enters the rectum, the outer shell dissolves and adheres to the rectal mucosa, and the contents are directly exposed to rectal fluid in the form of a solid powder and dissolve rapidly.

2. The ibuprofen suppository according to claim 1, characterized in that, The water-soluble matrix is ​​a mixture of polyethylene glycol 400 and polyethylene glycol 1000 in a mass ratio of (20-30):(80-70).

3. The ibuprofen suppository according to claim 2, characterized in that, The mass ratio of polyethylene glycol 400 to polyethylene glycol 1000 is 25:

75.

4. The ibuprofen suppository according to any one of claims 1-3, characterized in that, The bioadhesive material is carbomer, and its usage accounts for 1% to 2.0% of the total weight of the outer shell layer.

5. The ibuprofen suppository according to claim 4, characterized in that, The amount of carbomer used accounts for 1.0% to 1.5% of the total weight of the outer shell layer.

6. The ibuprofen suppository according to claim 1, characterized in that, The absorption enhancer is poloxamer 188, and the mass ratio of ibuprofen to poloxamer 188 is 1:(0.02-0.1).

7. The ibuprofen suppository according to claim 1 or 6, characterized in that, The contents also contain hydroxypropyl-β-cyclodextrin, and the ibuprofen forms an inclusion complex with the hydroxypropyl-β-cyclodextrin.

8. A method for preparing an ibuprofen suppository as described in any one of claims 1-7, characterized in that, Includes the following steps: (1) Shell preparation: The water-soluble matrix is ​​heated and melted, the bioadhesive material is added and stirred evenly, and then poured into the suppository mold while hot. The shaping component is inserted, and after cooling and solidification, the shaping component is pulled out to form a suppository shell with a hollow cavity. (2) Content preparation: Ibuprofen active ingredient and absorption promoter are mixed evenly, and hydroxypropyl-β-cyclodextrin is optionally added for inclusion treatment to obtain a solid powder content mixture; (3) Filling and sealing: Fill the hollow cavity obtained in step (1) with the mixture of contents obtained in step (2) in the form of solid powder, then seal with molten matrix, cool and demold to obtain the product.

9. The preparation method according to claim 8, characterized in that, The water-soluble matrix mentioned in step (1) is PEG. 400 and PEG 1000 The mixture is heated to a temperature of 65–75°C, and the shaping component is inserted to a depth of 1.5–2.5 cm from the end of the plug. The mixing method described in step (2) is grinding or air-jet milling, so that the particle size D of the mixture is... 90 Less than 20μm.

10. The use of the ibuprofen suppository as described in any one of claims 1-7 in the preparation of a medicament for treating fever or pain in children.

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