Ibuprofen pharmaceutical composition, and preparation method therefor and use thereof

Abstract

Disclosed are an ibuprofen pharmaceutical composition, and a preparation method therefor and the use thereof. The ibuprofen pharmaceutical composition comprises the following components: sustained-release pellets and immediate-release pellets, wherein the sustained-release pellets comprise ibuprofen, a filler and an adhesive; and the immediate-release pellets comprise ibuprofen, a filler, a suspending agent, a disintegrant, a flavoring agent and a pH regulator. The ibuprofen pharmaceutical composition takes effect quickly and can maintain a therapeutic effect for a long time. The administration compliance of children, elderly people and people with dysphagia can be effectively improved, and the administration frequency is reduced. A dry deposition particle has a wide loading range, and the presence of the dry deposition particle during drug storage and transportation is beneficial for maintaining the stability during drug storage and transportation. In addition, the ibuprofen pharmaceutical composition has the advantages of a simple preparation process, stable properties and convenient administration, and is suitable for industrial production.

Description

Ibuprofen pharmaceutical composition, preparation method and application thereof

[0001] This application claims priority to the prior application with patent application number 202311314293.6 filed with the State Intellectual Property Office of China on October 10, 2023, and with the invention name “Ibuprofen pharmaceutical composition, preparation method and application thereof”. Technical Field

[0002] The present invention relates to an ibuprofen pharmaceutical composition, a preparation method and application thereof. Background Art

[0003] Ibuprofen, also known as ibuprofen, is chemically called 2-(4-isobutylphenyl) propionic acid. It is a propionic acid derivative and a nonsteroidal anti-inflammatory analgesic. Its primary mechanism of action is through non-selective inhibition of cyclooxygenase (COX), thereby inhibiting the synthesis and release of prostaglandins. It also inhibits the release of inflammatory-stimulating substances from leukocytes and lysosomes, reducing pain impulses in local tissues and lowering the sensitivity of pain receptors. It has strong anti-inflammatory, anti-rheumatic, and antipyretic and analgesic effects.

[0004] Ibuprofen is also widely used clinically in the treatment of patent ductus arteriosus in newborns or premature infants. Studies have reported that it has similar or even stronger efficacy than indomethacin, better safety, and less renal damage. It is the first-line antipyretic drug for children.

[0005] Ibuprofen is widely used in the pharmaceutical field. Common ibuprofen preparations include ibuprofen tablets, ibuprofen sustained-release capsules, ibuprofen sustained-release tablets, and ibuprofen suspension. Common indications for ibuprofen include: 1. Relief of acute or persistent joint swelling and pain in various chronic arthritis conditions, such as rheumatoid arthritis, osteoarthritis, rheumatic arthritis, and gouty arthritis, without treating the underlying cause or controlling the course of the disease; 2. Treatment of various non-articular soft tissue rheumatic pain conditions, such as shoulder pain, tenosynovitis, bursitis, and muscle pain; 3. Acute mild to moderate pain, such as postoperative pain, post-traumatic pain, toothache, and headache; 4. Antipyretic effect on fever in adults and children.

[0006] Tablets and capsules are difficult to swallow for children, the elderly, and those with dysphagia. Suspensions can also be unstable and difficult to transport. Therefore, finding a stable, easy-to-take, and patient-compliant ibuprofen dosage form is an urgent technical challenge.

[0007] Summary of the Invention

[0008] The technical problem to be solved by the present invention is to provide an ibuprofen pharmaceutical composition, preparation method, and application thereof in order to overcome the shortcomings of the prior art, such as poor stability of ibuprofen suspension, high storage and transportation difficulties, ibuprofen tablets and capsules being unsuitable for children, the elderly, and other patients with dysphagia, and poor medication compliance. The ibuprofen pharmaceutical composition of the present invention has a rapid onset of action and can maintain a therapeutic effect for a long time, has good absorption and high bioavailability; can effectively improve medication compliance in children, the elderly, and those with dysphagia; has a wide range of dosages, which is conducive to ensuring drug stability during storage and transportation; and has a simple preparation process, stable properties, and is easy to take, making it suitable for industrial production.

[0009] The present invention provides an ibuprofen pharmaceutical composition, wherein the time to peak blood concentration (Tmax) is less than 5 hours and the duration is 8-12 hours; preferably, the time to peak blood concentration is less than 3 hours, further preferably less than 2.5 hours, and the duration is 8-11 hours; further preferably, the time to peak blood concentration is less than 2 hours, and the duration is 8-10 hours.

[0010] The present invention provides an ibuprofen pharmaceutical composition, comprising the following components: sustained-release pellets and rapid-release pellets, wherein the sustained-release pellets contain ibuprofen, a filler, and a binder; and the rapid-release pellets contain ibuprofen, a filler, a suspending agent, a disintegrant, a flavoring agent, and a pH regulator.

[0011] Preferably, the ibuprofen pharmaceutical composition has the peak time and sustained maintenance time of blood drug concentration as shown above.

[0012] In the present invention, the ibuprofen can be a conventional commercially available ibuprofen bulk drug, or an ibuprofen bulk drug prepared with reference to relevant literature.

[0013] According to an embodiment of the present invention, the content of ibuprofen can be 1.0% to 80.0%, for example 2.0% to 40.0%, and for example 5.0% to 30.0%, exemplified by 10.0%, 11.0%, 12.0%, 13.0%, 14.0%, 15.00%, 16.0%, 17.0%, 18.0%, 19.0%, 20.0% or 25.0%, wherein the content refers to the percentage of the mass of ibuprofen to the total mass of the ibuprofen pharmaceutical composition.

[0014] According to an embodiment of the present invention, the content of ibuprofen in the sustained-release pellets and the immediate-release pellets is the same or different. In some embodiments, the content of ibuprofen in the sustained-release pellets is greater than the content of ibuprofen in the immediate-release pellets, for example, the mass ratio is greater than 1.1:1, such as a mass ratio of (1.2 to 20):1, exemplified by 1.5:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1 or 19:1.

[0015] According to an embodiment of the present invention, the filler refers to a solid substance added to a material to improve material properties, increase volume, increase weight, and reduce material costs, and is selected from one or more of microcrystalline cellulose, pregelatinized starch, mannitol, sucrose, glucose, maltose, lactose, sorbitol, xylitol, maltitol, galactitol, erythritol, dextrin, and trehalose, for example, one or both of microcrystalline cellulose and mannitol. The sustained-release pellets and the immediate-release pellets may contain the same or different fillers.

[0016] According to an embodiment of the present invention, the content of the filler can be 1.0% to 85.0%, for example 10.0% to 70.0%, exemplified by 20.0%, 30.0%, 40.0%, 41.0%, 42.0%, 43.0%, 44.0%, 45.0%, 45.32%, 45.52%, 46.0%, 47.0%, 48.0%, 49.0%, 50.0%, 55.0%, 60.0%, 61.0%, 62.0%, 62.02%, 63.0%, 64.0%, 65.0%, 66.0%, 67.0%, 68.0%, 69.0%, 70.0% or 75.0%; the content refers to the percentage of the mass of the filler to the total mass of the ibuprofen pharmaceutical composition.

[0017] In some embodiments, the content of filler in the sustained-release pellets is less than that in the immediate-release pellets, for example, the mass ratio is 1:(1.5-4), for example, 1:2, 1:2.5, 1:2.6, 1:2.7, 1:3 or 1:3.5.

[0018] According to an embodiment of the present invention, the adhesive refers to various stress materials that connect or fit the same or different materials, selected from one or more of hydroxypropyl methylcellulose, carbomer, hydroxyethyl cellulose, polyethylene oxide, pregelatinized starch, copovidone, hydroxypropyl cellulose, ethyl cellulose, povidone (PVP) and sodium carboxymethyl cellulose.

[0019] According to an embodiment of the present invention, the suspending agent refers to a viscous hydrophilic colloid substance that can increase the viscosity of the dispersion medium to slow down the sedimentation rate of the particles, and adsorb on the surface of the particles to become a barrier to prevent the particles from agglomerating and clumping. It is selected from one or more of glycerol, gum arabic, agar, xanthan gum, colloidal microcrystalline cellulose, sodium alginate, microcrystalline cellulose-sodium carboxymethyl cellulose, sodium carboxymethyl cellulose and methyl cellulose.

[0020] According to an embodiment of the present invention, the disintegrant refers to an excipient that promotes the rapid disintegration of the drug into small particles in the gastrointestinal tract, and is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch and starch.

[0021] According to an embodiment of the present invention, the flavoring agent refers to a substance that acts as a flavoring agent, selected from one or more of aspartame, sucralose, fructose, sucrose, steviol glycosides, glycyrrhizin, citric acid, flavor, menthol, sodium chloride, neotame, acesulfame potassium, saccharin and saccharin sodium.

[0022] According to an embodiment of the present invention, the pH regulator refers to a substance that has a pH regulating effect, and is selected from one or more of citric acid, L-malic acid, sodium citrate, disodium hydrogen phosphate and sodium hydroxide.

[0023] According to an embodiment of the present invention, the content of ibuprofen in the sustained-release microcapsules can be 1.0% to 30.0%, for example 5.0% to 20.0%, exemplified by 15.00%, 14.00%, 13.00%, 12.00%, 11.00%, 10.00%, 9.00%, 8.00%, 7.00% or 6.00%, wherein the content refers to the percentage of the mass of ibuprofen in the sustained-release microcapsules to the total mass of the ibuprofen pharmaceutical composition.

[0024] According to some embodiments of the present invention, in the sustained-release pellets, the filler may be microcrystalline cellulose.

[0025] According to an embodiment of the present invention, the content of the filler in the sustained-release microcapsules can be 1.0% to 30.0%, for example 5.0% to 20.0%, exemplified by 10.00%, 11.00%, 12.00%, 12.44%, 13.00%, 14.00%, 15.00%, 16.00%, 17.00%, 18.00% or 19.00%, wherein the content refers to the percentage of the mass of the filler in the sustained-release microcapsules to the total mass of the ibuprofen pharmaceutical composition.

[0026] According to some embodiments of the present invention, in the sustained-release pellets, the binder may be povidone.

[0027] According to an embodiment of the present invention, the content of the binder in the sustained-release microcapsules can be 0.1% to 10.0%, for example 0.1% to 5.0%, exemplified by 0.2%, 0.3%, 0.4%, 0.5%, 0.56%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 2.0%, 3.0%, and 4.0%. The content refers to the percentage of the mass of the binder in the sustained-release microcapsules to the total mass of the ibuprofen pharmaceutical composition.

[0028] According to an embodiment of the present invention, the content of ibuprofen in the rapid-release micropills can be 1.00% to 10.00%, for example, 9.00%, 8.00%, 7.00%, 6.00%, 5.00%, 4.00%, 3.00%, 2.00% or 1.00%, and the content refers to the percentage of the mass of ibuprofen in the rapid-release micropills to the total mass of the ibuprofen pharmaceutical composition.

[0029] According to some embodiments of the present invention, in the rapid-release pellets, the filler may be microcrystalline cellulose and / or mannitol.

[0030] According to an embodiment of the present invention, the content of the filler in the rapid-release microcapsules can be 1.0% to 80.0%, for example, 10.0% to 55.0%, exemplified by 20.0%, 25.0%, 26.0%, 27.0%, 28.0%, 29.0%, 30.0%, 31.0%, 32.0%, 33.0%, 33.08%, 33.5%, 34.0%, 35.0%, 36.0%, 37.0%, 38.0%, 39.0%, 40.0%, 45.0%, 49.13%, 49.58% or 50.0%, wherein the content refers to the percentage of the mass of the filler in the rapid-release microcapsules to the total mass of the ibuprofen pharmaceutical composition.

[0031] According to some embodiments of the present invention, in the rapid-release pellets, the suspending agent may be xanthan gum and / or microcrystalline cellulose-sodium carboxymethyl cellulose.

[0032] According to an embodiment of the present invention, the content of the suspending agent can be 1.0% to 30.0%, for example 5.0% to 20.0%, exemplified by 6.0%, 7.0%, 8.0%, 9.0%, 10.0%, 10.75%, 11.0%, 12.0%, 13.0%, 14.0%, 15.0%, 16.0%, 17.0%, 18.0% or 19.0%, wherein the content refers to the percentage of the mass of the suspending agent to the total mass of the ibuprofen pharmaceutical composition.

[0033] According to some embodiments of the present invention, in the rapid-release pellets, the disintegrant may be sodium starch glycolate.

[0034] According to an embodiment of the present invention, the content of the disintegrant can be 1.0% to 20.0%, for example 5.0% to 15.0%, exemplified by 6.0%, 7.0%, 8.0%, 8.50%, 9.0%, 10.0%, 10.75%, 11.0%, 12.0%, 13.0% or 14.0%, where the content refers to the percentage of the mass of the disintegrant to the total mass of the ibuprofen pharmaceutical composition.

[0035] According to some embodiments of the present invention, in the rapid-release pellets, the flavoring agent may be essence (eg, strawberry essence) and / or aspartame.

[0036] According to an embodiment of the present invention, the content of the flavoring agent can be 1.0% to 10.0%, for example, 1.50%, 2.0%, 2.50%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0% or 9.0%, and the content refers to the percentage of the mass of the flavoring agent to the total mass of the ibuprofen pharmaceutical composition.

[0037] According to some embodiments of the present invention, in the rapid-release pellets, the pH regulator may be citric acid.

[0038] According to an embodiment of the present invention, the content of the pH regulator can be 0.10% to 5.00%, for example 0.10% to 2.00%, exemplified by 0.20%, 0.30%, 0.40%, 0.50%, 0.60%, 0.67%, 0.70%, 0.80%, 0.90%, 1.00% or 1.50%, wherein the content refers to the percentage of the mass of the pH regulator to the total mass of the ibuprofen pharmaceutical composition.

[0039] According to a preferred embodiment of the present invention, the sustained-release pellets comprise the following components or are mainly composed of the following components: each component adopts a mass fraction of 1.00% to 30.00% ibuprofen, 1.00% to 30.00% microcrystalline cellulose, and 0.1% to 10.00% povidone, where the mass fraction refers to the percentage of the mass of each component to the total mass of the ibuprofen pharmaceutical composition;

[0040] Furthermore, the sustained-release microcapsules contain the following components or are mainly composed of the following components: each component is expressed in mass fractions of 5.00% to 20.00% ibuprofen, 5.00% to 20.00% microcrystalline cellulose, and 0.1% to 5.00% povidone, where the mass fractions refer to the percentage of the mass of each component to the total mass of the ibuprofen pharmaceutical composition.

[0041] According to an embodiment of the present invention, the sustained-release pellets may be any of the following formulations:

[0042] Prescription 1: 10.00% ibuprofen, 12.44% microcrystalline cellulose and 0.56% povidone, the percentages being the mass of each component relative to the total mass of the ibuprofen pharmaceutical composition;

[0043] Prescription 2: 9.00% ibuprofen, 12.44% microcrystalline cellulose, and 0.56% povidone, where the percentages refer to the mass of each component as a percentage of the total mass of the ibuprofen pharmaceutical composition;

[0044] Prescription 3: 12.00% ibuprofen, 12.44% microcrystalline cellulose and 0.56% povidone, the percentages being the mass of each component relative to the total mass of the ibuprofen pharmaceutical composition;

[0045] Prescription 4: 14.00% ibuprofen, 12.44% microcrystalline cellulose and 0.56% povidone, the percentages mentioned refer to the percentage of the mass of each component to the total mass of the ibuprofen pharmaceutical composition.

[0046] According to an embodiment of the present invention, the mass ratio of the sustained-release pellets to the immediate-release pellets can be 1:100 to 100:1, or 1:5 to 5:1, for example, 23:77, 11:39, 1:3, 27:73 or 7:18.

[0047] According to a preferred embodiment of the present invention, the rapid-release micropills contain the following components or are mainly composed of the following components: each component is expressed in mass fractions, 1.00% to 10.00% ibuprofen, 1.00% to 80.00% microcrystalline cellulose and / or mannitol, 1.00% to 30.00% xanthan gum and / or microcrystalline cellulose-sodium carboxymethyl cellulose, 1.00% to 20.00% sodium starch glycolate, 1.00% to 10.00% flavor and / or aspartame, 0.10% to 5.00% citric acid; the mass fractions refer to the percentage of the mass of each component to the total mass of the ibuprofen composition;

[0048] Furthermore, the rapid-release microcapsules contain the following components or are mainly composed of the following components: each component is expressed in mass fraction, 1.00% to 10.00% ibuprofen, 20.00% to 40.00% microcrystalline cellulose, 10.00% to 25.00% mannitol, 1.00% to 10.00% xanthan gum, 1.00% to 15.00% microcrystalline cellulose-sodium carboxymethyl cellulose, 1.00% to 15.00% sodium starch glycolate, 1.00% to 10.00% flavor and / or aspartame, 0.10% to 5.00% citric acid; the mass fraction refers to the percentage of the mass of each component to the total mass of the ibuprofen composition.

[0049] According to an embodiment of the present invention, the rapid-release pellets may be formulated in any of the following ways:

[0050] Formulation 1: 5.00% ibuprofen, 2.00% xanthan gum, 8.75% microcrystalline cellulose-sodium carboxymethyl cellulose, 33.08% microcrystalline cellulose, 16.50% mannitol, 8.50% sodium carboxymethyl starch, 0.67% citric acid, 2.00% strawberry flavor, and 0.50% aspartame. The percentages refer to the mass of each component as a percentage of the total mass of the ibuprofen pharmaceutical composition.

[0051] Formulation 2: 6.00% ibuprofen, 2.00% xanthan gum, 8.75% microcrystalline cellulose-sodium carboxymethyl cellulose, 33.08% microcrystalline cellulose, 16.50% mannitol, 8.50% sodium carboxymethyl starch, 0.67% citric acid, 2.00% strawberry flavor, and 0.50% aspartame. The percentages refer to the mass of each component as a percentage of the total mass of the ibuprofen pharmaceutical composition.

[0052] Formulation 3: 3.00% ibuprofen, 2.00% xanthan gum, 8.75% microcrystalline cellulose-sodium carboxymethyl cellulose, 33.08% microcrystalline cellulose, 16.50% mannitol, 8.50% sodium carboxymethyl starch, 0.67% citric acid, 2.00% strawberry flavor, and 0.50% aspartame. The percentages refer to the mass of each component as a percentage of the total mass of the ibuprofen pharmaceutical composition.

[0053] Formulation 4: 1.00% ibuprofen, 2.00% xanthan gum, 8.75% microcrystalline cellulose-sodium carboxymethyl cellulose, 33.08% microcrystalline cellulose, 16.50% mannitol, 8.50% sodium carboxymethyl starch, 0.67% citric acid, 2.00% strawberry flavor and 0.50% aspartame. The percentages refer to the percentage of the mass of each component to the total mass of the ibuprofen pharmaceutical composition.

[0054] The present invention also provides a method for preparing the ibuprofen pharmaceutical composition, comprising the following steps:

[0055] The components of the above-mentioned sustained-release micropellets are mixed, wet granulated, and a soft material is prepared and then extruded and spheronized to obtain sustained-release micropellets;

[0056] The components of the above-mentioned rapid-release pellets are mixed, wet granulated, and a soft material is prepared and then extruded and spheronized to obtain rapid-release pellets;

[0057] Then, the sustained-release pellets and the quick-release pellets are mixed according to a certain ratio to obtain the ibuprofen pharmaceutical composition.

[0058] The present invention also provides an ibuprofen pharmaceutical composition prepared by the preparation method of the ibuprofen pharmaceutical composition.

[0059] The present invention also provides use of the ibuprofen pharmaceutical composition in preparing a medicament for treating and / or alleviating mild to moderate pain diseases.

[0060] According to an embodiment of the present invention, the drug is a suspension preparation, for example, a dry suspension preparation.

[0061] The present invention also provides a method for treating and / or alleviating mild to moderate pain diseases, comprising administering a therapeutically effective amount of the ibuprofen pharmaceutical composition to a patient in need thereof.

[0062] According to an embodiment of the present invention, the interval between each administration is 8 to 12 hours; further, the administration dosage is 140 to 160 mg / time, for example, the administration dosage is 150 mg / time.

[0063] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0064] The reagents and raw materials used in the present invention are commercially available.

[0065] Beneficial effects of the present invention:

[0066] The ibuprofen pharmaceutical composition prepared by the present invention has a rapid onset of action and can maintain a therapeutic effect for a long time, has good absorption and high bioavailability, can effectively improve the medication compliance of children, the elderly and people with dysphagia, has a wide range of dosage amounts of dry mixed suspension granules, exists in the form of dry mixed granules during storage and transportation, and is conducive to ensuring the stability of the drug during storage and transportation, and has a simple preparation process, stable properties, and is easy to take, making it suitable for industrial production.

[0067] Definitions and Explanations of Terms

[0068] The term "pellet" refers to small pellets or granules made from raw materials through a formulation process.

[0069] The term "plurality" refers to a physical mixture of two or more species, for example, a physical mixture of two, three or more species.

[0070] The term "mainly composed of..." means that the sum of the masses of these components accounts for not less than 85% of the total mass of the ibuprofen pharmaceutical composition, for example not less than 90%, exemplified by 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%.

[0071] The term "microcrystalline cellulose-sodium carboxymethyl cellulose" is a compound of microcrystalline cellulose and sodium carboxymethyl cellulose, not a physical mixture.

[0072] The term "patient" refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

[0073] The term "therapeutically effective amount" refers to that amount of an active compound or drug that elicits the biological or medical response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician. BRIEF DESCRIPTION OF THE DRAWINGS

[0074] Figure 1 shows the dissolution profile of the reference preparation commercially available Merlin at pH 5.5;

[0075] FIG2 shows the dissolution curve of the ibuprofen pharmaceutical composition prepared in Example 2 at pH 5.5;

[0076] FIG3 shows the dissolution curve of the ibuprofen pharmaceutical composition prepared in Example 3 at pH 5.5;

[0077] FIG4 shows the dissolution curve of the ibuprofen pharmaceutical composition prepared in Example 4 at pH 5.5;

[0078] FIG5 shows the dissolution curve of the ibuprofen pharmaceutical composition prepared in Example 5 at pH 5.5;

[0079] FIG6 shows the dissolution curve of the ibuprofen pharmaceutical composition prepared in Example 6 at pH 5.5;

[0080] FIG7 shows a drug-time curve of the ibuprofen pharmaceutical composition obtained in Example 3 and the commercially available product Merlin, wherein The drug-time curve diagram of the ibuprofen pharmaceutical composition prepared in Example 3 is shown. A graph showing the concentration-time curve of the commercially available product Motrin.

[0081] FIG8 shows a drug-time curve of the ibuprofen pharmaceutical composition obtained in Example 6 and the commercially available product Merlin, wherein The drug-time curve diagram of the ibuprofen pharmaceutical composition prepared in Example 6 is shown. A graph showing the concentration-time curve of the commercially available product Motrin.

[0082] FIG9 is a drug-time curve of the ibuprofen pharmaceutical composition prepared in the comparative example. DETAILED DESCRIPTION

[0083] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

[0084] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available, or can be prepared by known methods, or selected according to commercial specifications.

[0085] Example 1: Dissolution test of reference preparation

[0086] The reference preparation used was the commercially available preparation Merlin (ibuprofen immediate-release suspension, Shanghai Johnson & Johnson Pharmaceutical Co., Ltd.). The dissolution conditions were paddle method at 65 rpm and medium pH 5.5 phosphate buffer. The sample dissolution data results are shown in Table 1, and the dissolution curve is shown in Figure 1.

[0087] Table 1 Dissolution data of commercially available ibuprofen suspension

[0088] Example 2: Ibuprofen pharmaceutical composition

[0089] Table 2-1 Prescription of Example 2

[0090] Preparation method:

[0091] Sustained-release pellets:

[0092] 1) Prescription weighing: Accurately weigh ibuprofen, microcrystalline cellulose, and povidone according to the mass ratio;

[0093] 2) Soft material preparation: The materials from step 1) were added to a wet granulator and mixed at a stirring speed of 180 rpm and a chopping speed of 540 rpm for 3 minutes. The parameters were then set to: stirring speed 180 rpm, chopping speed 1200 rpm, the instrument was turned on, and a certain amount of water (approximately 80% of the prescribed amount) was added at a pump speed of 95 rpm for 4 ± 0.5 minutes to prepare the soft material.

[0094] 3) Preparation of sustained-release pellets: The soft material prepared in step 2) was placed in an extruder and extruded at a speed of 40 rpm. The extrudate was poured into a spheronizer at 800 rpm and spheronized for 120 seconds to obtain sustained-release pellets.

[0095] Immediate-release pellets:

[0096] 4) Prescription weighing: Accurately weigh the ingredients of the immediate-release pellets according to the mass ratio;

[0097] 5) Soft material preparation: The material from step 4) was added to a wet granulator and mixed at a stirring speed of 180 rpm and a chopping speed of 540 rpm for 3 minutes. The parameters were then set to: stirring speed 180 rpm, chopping speed 1500 rpm, the instrument was turned on, and a certain amount of water (approximately 55% of the prescribed amount) was added at a pump speed of 95 rpm for 4 ± 1 minutes to prepare the soft material.

[0098] 6) Preparation of immediate-release pellets: The soft material prepared in step 5) was placed in an extruder and extruded at a speed of 40 rpm. The extrudate was poured into a spheronizer at 800 rpm and spheronized for 60 seconds to obtain immediate-release pellets.

[0099] 7) Mixing the prepared sustained-release pellets and immediate-release pellets to obtain an ibuprofen pharmaceutical composition.

[0100] The dissolution conditions were paddle method at 65 rpm and pH 5.5 citrate buffer. The dissolution data of the prepared ibuprofen pharmaceutical composition sample are shown in Table 2-2, and the dissolution curve is shown in Figure 2.

[0101] Table 2-2 Ibuprofen pharmaceutical composition dissolution data table

[0102] Example 3: Ibuprofen Pharmaceutical Composition

[0103] Table 3-1 Prescription of Example 3

[0104] Preparation method:

[0105] Sustained-release pellets:

[0106] 1) Prescription weighing: Accurately weigh ibuprofen, microcrystalline cellulose, and povidone according to the mass ratio;

[0107] 2) Soft material preparation: The material from step 1) was added to a wet granulator and mixed at a stirring speed of 180 rpm and a chopping speed of 540 rpm for 3 minutes. The parameters were then set to: stirring speed 180 rpm, chopping speed 1200 rpm, the instrument was turned on, and a certain amount of water (approximately 80% of the prescribed amount) was added at a pump speed of 95 rpm for 4 ± 0.5 minutes to prepare the soft material.

[0108] 3) Preparation of sustained-release pellets: The soft material prepared in step 2) was placed in an extruder and extruded at a speed of 40 rpm. The extrudate was poured into a spheronizer at 800 rpm and spheronized for 120 seconds to obtain sustained-release pellets.

[0109] Immediate-release pellets:

[0110] 4) Prescription weighing: Accurately weigh the ingredients of the immediate-release pellets according to the mass ratio;

[0111] 5) Soft material preparation: The material from step 4) was added to a wet granulator and mixed at a stirring speed of 180 rpm and a chopping speed of 540 rpm for 3 minutes. The parameters were then set to: stirring speed 180 rpm, chopping speed 1500 rpm, the instrument was turned on, and a certain amount of water (approximately 55% of the prescribed amount) was added at a pump speed of 95 rpm for 4 ± 1 minutes to prepare the soft material.

[0112] 6) Preparation of micropellets: The soft material prepared in step 5) was placed in an extruder and extruded at a speed of 40 rpm. The extrudate was poured into a spheronizer at 800 rpm and spheronized for 60 seconds to obtain immediate-release micropellets.

[0113] 7) Mixing the prepared sustained-release pellets and immediate-release pellets to obtain an ibuprofen pharmaceutical composition.

[0114] The dissolution conditions were paddle method at 65 rpm and pH 5.5 citrate buffer. The dissolution data of the prepared ibuprofen pharmaceutical composition sample are shown in Table 3-2, and the dissolution curve is shown in FIG3 .

[0115] Table 3-2 Ibuprofen pharmaceutical composition dissolution data

[0116] Example 4: Ibuprofen Pharmaceutical Composition

[0117] Table 4-1 Prescription of Example 4

[0118] Preparation method:

[0119] Sustained-release pellets:

[0120] 1) Prescription weighing: Accurately weigh ibuprofen, microcrystalline cellulose, and povidone according to the mass ratio;

[0121] 2) Soft material preparation: The materials from step 1) were added to a wet granulator and mixed at a stirring speed of 180 rpm and a chopping speed of 540 rpm for 3 minutes. The parameters were then set to: stirring speed 180 rpm, chopping speed 1200 rpm, the instrument was turned on, and a certain amount of water (approximately 80% of the prescribed amount) was added at a pump speed of 95 rpm for 4 ± 0.5 minutes to prepare the soft material.

[0122] 3) Preparation of sustained-release pellets: The soft material prepared in step 2) was placed in an extruder and extruded at a speed of 40 rpm. The extrudate was poured into a spheronizer at 800 rpm and spheronized for 120 seconds to obtain sustained-release pellets.

[0123] Immediate-release pellets:

[0124] 4) Prescription weighing: Accurately weigh the ingredients of the immediate-release pellets according to the mass ratio;

[0125] 5) Soft material preparation: The material from step 4) was added to a wet granulator and mixed at a stirring speed of 180 rpm and a chopping speed of 540 rpm for 3 minutes. The parameters were then set to: stirring speed 180 rpm, chopping speed 1500 rpm, the instrument was turned on, and a certain amount of water (approximately 55% of the prescribed amount) was added at a pump speed of 95 rpm for 4 ± 1 minutes to prepare the soft material.

[0126] 6) Preparation of immediate-release pellets: The soft material prepared in step 5) was placed in an extruder and extruded at a speed of 40 rpm. The extrudate was poured into a spheronizer at 800 rpm and spheronized for 60 seconds to obtain immediate-release pellets.

[0127] 7) Mixing the prepared sustained-release pellets and immediate-release pellets to obtain an ibuprofen pharmaceutical composition.

[0128] The dissolution conditions were paddle method at 65 rpm and pH 5.5 citrate buffer. The dissolution data of the prepared ibuprofen pharmaceutical composition sample are shown in Table 4-2, and the dissolution curve is shown in FIG4 .

[0129] Table 4-2 Dissolution data of ibuprofen pharmaceutical composition

[0130] Example 5: Ibuprofen Pharmaceutical Composition

[0131] Table 5-1 Prescription of Example 5

[0132] Preparation method:

[0133] Sustained-release pellets:

[0134] 1) Prescription weighing: Accurately weigh ibuprofen, microcrystalline cellulose, and povidone according to the mass ratio;

[0135] 2) Soft material preparation: The materials from step 1) were added to a wet granulator and mixed at a stirring speed of 180 rpm and a chopping speed of 540 rpm for 3 minutes. The parameters were then set to: stirring speed 180 rpm, chopping speed 1200 rpm, the instrument was turned on, and a certain amount of water (approximately 80% of the prescribed amount) was added at a pump speed of 95 rpm for 4 ± 0.5 minutes to prepare the soft material.

[0136] 3) Preparation of sustained-release pellets: The soft material prepared in step 2) was placed in an extruder and extruded at a speed of 40 rpm. The extrudate was poured into a spheronizer at 800 rpm and spheronized for 120 seconds to obtain sustained-release pellets.

[0137] Immediate-release pellets:

[0138] 4) Prescription weighing: Accurately weigh the ingredients of the immediate-release pellets according to the mass ratio;

[0139] 5) Soft material preparation: The excipients from step 1) were added to a wet granulator and mixed at a stirring speed of 180 rpm and a chopping speed of 540 rpm for 3 minutes. The parameters were then set to: stirring speed 180 rpm, chopping speed 1500 rpm, the instrument was turned on, and a certain amount of water (approximately 55% of the prescribed amount) was added at a pump speed of 95 rpm for 4 ± 1 minutes to prepare the soft material.

[0140] 6) Preparation of immediate-release pellets: The soft material prepared in step 5) was placed in an extruder and extruded at a speed of 40 rpm. The extrudate was poured into a spheronizer at 800 rpm and spheronized for 60 seconds to obtain immediate-release pellets.

[0141] 7) Mixing the prepared sustained-release pellets and immediate-release pellets to obtain an ibuprofen pharmaceutical composition.

[0142] The dissolution conditions were paddle method at 65 rpm and pH 5.5 citrate buffer. The dissolution data of the prepared ibuprofen pharmaceutical composition are shown in Table 5-2, and the dissolution curve is shown in FIG5 .

[0143] Table 5-2 Ibuprofen pharmaceutical composition dissolution data table

[0144] Example 6: Ibuprofen Pharmaceutical Composition

[0145] Table 6-1 Prescription of Example 6

[0146] Preparation method:

[0147] Sustained-release pellets:

[0148] 1) Prescription weighing: Accurately weigh ibuprofen, microcrystalline cellulose, and povidone according to the mass ratio;

[0149] 2) Soft material preparation: The materials from step 1) were added to a wet granulator and mixed at a stirring speed of 100 rpm and a chopping speed of 500 rpm for 5 minutes. The parameters were then set to: stirring speed 100 rpm, chopping speed 800 rpm, the instrument was turned on, and a certain amount of water (approximately 60% of the prescribed amount) was added at a pump speed of 95 rpm for 3 ± 1 minutes to prepare the soft material.

[0150] 3) Preparation of sustained-release pellets: The soft material prepared in step 2) was placed in an extruder and extruded at a speed of 50 rpm. The extrudate was poured into a spheronizer at 800 rpm and spheronized for 120 seconds to obtain sustained-release pellets.

[0151] Immediate-release pellets:

[0152] 4) Prescription weighing: Accurately weigh the ingredients of the immediate-release pellets according to the mass ratio;

[0153] 5) Soft Material Preparation: The material from step 4) was added to a wet granulator and mixed at a stirring speed of 100 rpm and a chopping speed of 500 rpm for 5 minutes. The parameters were then set to: stirring speed 100 rpm, chopping speed 1000 rpm, the instrument was turned on, and a certain amount of water (approximately 50% of the prescribed amount) was added at a pump speed of 95 rpm for 3 ± 1 minutes to prepare the soft material.

[0154] 6) Preparation of immediate-release pellets: The soft material prepared in step 5) was placed in an extruder and extruded at a speed of 70 rpm. The extrudate was poured into a spheronizer at 800 rpm and spheronized for 60 seconds to obtain immediate-release pellets.

[0155] 7) Mixing the prepared sustained-release pellets and immediate-release pellets to obtain an ibuprofen pharmaceutical composition.

[0156] The dissolution conditions were paddle method at 65 rpm and pH 5.5 citrate buffer. The dissolution data of the prepared ibuprofen pharmaceutical composition sample are shown in Table 6-2, and the dissolution curve is shown in FIG6 .

[0157] Table 6-2 Ibuprofen pharmaceutical composition dissolution data

[0158] Inspection of related substances: High performance liquid chromatography equipped with a UV detector, using a Waters XTERRA MS C18, 150 mm × 4.6 mm, 5 μm column, 0.02 mol / L sodium dihydrogen phosphate buffer as the mobile phase and diluent, and an injection volume of 30 μl.

[0159] Table 7 Data of related substances of ibuprofen pharmaceutical composition

[0160] Other inspections: According to the quality requirements of dry suspensions, the sample prepared in Example 6 was inspected for content, content uniformity, and sedimentation volume ratio. The results are shown in Table 8.

[0161] Table 8 Data table of ibuprofen pharmaceutical composition content, content uniformity and sedimentation volume ratio

[0162] Experimental Example 7

[0163] The sample prepared in Example 3 was compared with the commercially available product in Example 1 (trade name: Motrin, immediate-release suspension) in a clinical trial under fasting conditions in 12 healthy Chinese adult subjects. The sample prepared in Example 3 was administered once every 12 hours, and the commercially available preparation in Example 1 was administered once every 6 hours, or twice every 12 hours. The results are shown in Table 9, and the drug-time curve is shown in Figure 7.

[0164] Example 3 Administration of the ibuprofen pharmaceutical composition: The ibuprofen pharmaceutical composition (containing 150 mg of ibuprofen) was brewed with 15 ml of water and then taken orally.

[0165] Table 9 Comparison of clinical results between commercially available preparations and the product of Example 3

[0166] Experimental Example 8

[0167] The sample prepared in Example 6 was compared with the commercially available product in Example 1 (trade name: Motrin, immediate-release suspension) in a clinical trial under fasting conditions in 12 healthy Chinese adult subjects. The sample prepared in Example 6 was administered once every 12 hours, while the commercially available preparation was administered once every 6 hours, or twice every 12 hours. The results are shown in Table 10, and the drug-time curve is shown in Figure 8.

[0168] Example 6 Administration of the ibuprofen pharmaceutical composition: The ibuprofen pharmaceutical composition (containing 150 mg of ibuprofen) was brewed with 15 ml of water and then taken orally.

[0169] Table 10 Comparison of clinical results between commercially available preparations and the product of Example 6

[0170] Comparative Example

[0171] The product of Example 8 in CN115702883A was clinically tested on 12 healthy Chinese adult subjects under fasting conditions. The comparative sample was administered once every 12 hours. The results are shown in Table 11 and the drug-time curve is shown in Figure 9.

[0172] Table 11 Comparison of clinical results between commercially available preparations and comparative example products

[0173] As can be seen from Examples 1 to 6, the ibuprofen composition prepared by the present invention can achieve a 12-hour sustained release, and the dry suspension can be converted into a suspension granule after adding water, which is more convenient to swallow. The drug can maintain an effective concentration in the body for a longer period of time, thereby reducing the drug dosage, improving the efficacy, prolonging the drug action time, and reducing adverse drug reactions.

[0174] It can be seen from Experimental Examples 7 to 8 that the ibuprofen composition provided by the present invention is compared with the commercially available ibuprofen suspension preparation (trade name: Merlin, manufacturer: Shanghai Johnson & Johnson Pharmaceutical Co., Ltd.), and it is found that the single administration of the sample is C max It is similar to other drugs and can take effect quickly, reduce the number of medications, improve patient compliance, and is suitable for pediatric patients, with good market prospects.

[0175] According to the human pharmacokinetic data of the comparative example, the present invention can significantly increase the time for the blood drug concentration to reach the peak compared with the comparative example, thereby being able to take effect quickly, while the comparative example takes effect slowly, which is not conducive to the patient's rapid fever reduction.

[0176] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.

Claims

1. An ibuprofen pharmaceutical composition, characterized in that: The blood concentration of the ibuprofen pharmaceutical composition reaches a peak time of less than 5 hours and is maintained for 8 hours to 12 hours; Preferably, the peak time of the blood drug concentration is less than 3 hours (preferably less than 2.5 hours) and the duration is 8-11 hours; It is further preferred that the peak time of the blood drug concentration is less than 2 hours and the duration is 8 hours to 10 hours; And / or, the ibuprofen pharmaceutical composition comprises the following components: sustained-release pellets and rapid-release pellets, wherein the sustained-release pellets comprise ibuprofen, a filler and a binder; and the rapid-release pellets comprise ibuprofen, a filler, a suspending agent, a disintegrant, a flavoring agent and a pH regulator.

2. The ibuprofen pharmaceutical composition according to claim 1, wherein: The content of ibuprofen is 1.0% to 80.0%, and the content refers to the percentage of the mass of the ibuprofen to the total mass of the ibuprofen pharmaceutical composition; and / or, The mass ratio of the sustained-release pellets to the immediate-release pellets is 1:100 to 100:

1.

3. The ibuprofen pharmaceutical composition according to claim 1, wherein: The filler is selected from one or more of microcrystalline cellulose, pregelatinized starch, mannitol, sucrose, glucose, maltose, lactose, sorbitol, xylitol, maltitol, galactitol, erythritol, dextrin and trehalose; and / or, The binder is selected from one or more of hydroxypropyl methylcellulose, carbomer, hydroxyethyl cellulose, polyoxyethylene, pregelatinized starch, copovidone, hydroxypropyl cellulose, ethyl cellulose, povidone and sodium carboxymethyl cellulose; and / or, The suspending agent is selected from one or more of glycerol, gum arabic, agar, xanthan gum, colloidal microcrystalline cellulose, sodium alginate, sodium carboxymethyl cellulose, microcrystalline cellulose-sodium carboxymethyl cellulose and methyl cellulose; and / or, The disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch and starch; and / or, The flavoring agent is selected from one or more of aspartame, sucralose, fructose, sucrose, steviol glycosides, glycyrrhizin, citric acid, flavor, menthol, sodium chloride, neotame, acesulfame potassium, saccharin and saccharin sodium; and / or, The pH regulator is selected from one or more of citric acid, L-malic acid, sodium citrate, disodium hydrogen phosphate and sodium hydroxide.

4. The ibuprofen pharmaceutical composition according to claim 1, wherein: In the sustained-release pellets, the filler is microcrystalline cellulose; and / or, In the sustained-release pellets, the binder is povidone; Preferably, in the sustained-release pellets, the content of ibuprofen is 1.0% to 30.0%, and the content refers to the percentage of the mass of the ibuprofen to the total mass of the ibuprofen pharmaceutical composition; and / or, In the sustained-release pellets, the content of the filler is 1.0% to 30.0%, and the content refers to the percentage of the mass of the filler to the total mass of the ibuprofen pharmaceutical composition; and / or, In the sustained-release pellets, the content of the binder is 0.1% to 10.0%, and the content refers to the percentage of the mass of the binder to the total mass of the ibuprofen pharmaceutical composition.

5. The ibuprofen pharmaceutical composition according to claim 1, wherein: In the rapid-release pellets, the filler is microcrystalline cellulose and / or mannitol; and / or, In the rapid-release pellets, the suspending agent is xanthan gum and / or microcrystalline cellulose-sodium carboxymethyl cellulose; and / or, In the instant-release pellets, the disintegrant is sodium carboxymethyl starch; and / or, In the rapid-release pellets, the flavoring agent is flavor and / or aspartame; and / or, In the rapid-release pellets, the pH regulator is citric acid; In the rapid-release pellets, the content of ibuprofen is 1.00% to 10.00%, and the content refers to the percentage of the mass of the ibuprofen to the total mass of the ibuprofen pharmaceutical composition.

6. The ibuprofen pharmaceutical composition according to claim 1, wherein: The content of the filler is 1.0% to 80.0%, and the content refers to the percentage of the mass of the filler to the total mass of the ibuprofen pharmaceutical composition; and / or, The content of the suspending agent is 1.0% to 30.0%, and the content refers to the percentage of the mass of the suspending agent to the total mass of the ibuprofen pharmaceutical composition; and / or, The content of the disintegrant is 1.0% to 20.0%, and the content refers to the percentage of the mass of the disintegrant to the total mass of the ibuprofen pharmaceutical composition; and / or, The content of the flavoring agent is 1.0% to 10.0%, and the content refers to the percentage of the mass of the flavoring agent to the total mass of the ibuprofen pharmaceutical composition; and / or, The content of the pH regulator is 0.10% to 5.00%, and the content refers to the percentage of the mass of the pH regulator to the total mass of the ibuprofen pharmaceutical composition.

7. The ibuprofen pharmaceutical composition according to claim 1, wherein: The sustained-release pellets contain the following components: each component adopts a mass fraction of 1.00% to 30.00% ibuprofen, 1.00% to 30.00% microcrystalline cellulose, and 0.10% to 10.00% povidone, and the mass fraction refers to the percentage of the mass of each component to the total mass of the ibuprofen pharmaceutical composition; and / or, The rapid-release pellets contain the following components: each component is measured in mass fraction, 1.00% to 10.00% ibuprofen, 1.00% to 80.00% microcrystalline cellulose and / or mannitol, 1.00% to 30.00% xanthan gum and / or microcrystalline cellulose-sodium carboxymethyl cellulose, 1.00% to 20.00% sodium carboxymethyl starch, 1.00% to 10.00% flavor and / or aspartame, 0.10% to 5.00% citric acid; the mass fraction refers to the percentage of the mass of each component to the total mass of the ibuprofen composition.

8. The ibuprofen pharmaceutical composition according to claim 1, wherein: The sustained-release pellets are any of the following prescriptions: Prescription 1: 10.00% ibuprofen, 12.44% microcrystalline cellulose and 0.56% povidone, the percentages being the percentage of the mass of each component to the total mass of the ibuprofen pharmaceutical composition; Prescription 2: 9.00% ibuprofen, 12.44% microcrystalline cellulose and 0.56% povidone, the percentages being the percentage of the mass of each component to the total mass of the ibuprofen pharmaceutical composition; Prescription 3: 12.00% ibuprofen, 12.44% microcrystalline cellulose and 0.56% povidone, the percentages being the percentage of the mass of each component to the total mass of the ibuprofen pharmaceutical composition; Prescription 4: 14.00% ibuprofen, 12.44% microcrystalline cellulose and 0.56% povidone, the percentages refer to the percentage of the mass of each component to the total mass of the ibuprofen pharmaceutical composition; and / or, The rapid-release pellets are any of the following formulations: Formula 1: 5.00% ibuprofen, 2.00% xanthan gum, 8.75% microcrystalline cellulose-sodium carboxymethyl cellulose, 33.08% microcrystalline cellulose, 16.50% mannitol, 8.50% sodium carboxymethyl starch, 0.67% citric acid, 2.00% strawberry flavor and 0.50% aspartame, wherein the percentage refers to the percentage of the mass of each component to the total mass of the ibuprofen pharmaceutical composition; Formula 2: 6.00% ibuprofen, 2.00% xanthan gum, 8.75% microcrystalline cellulose-sodium carboxymethyl cellulose, 33.08% microcrystalline cellulose, 16.50% mannitol, 8.50% sodium carboxymethyl starch, 0.67% citric acid, 2.00% strawberry flavor and 0.50% aspartame, wherein the percentage refers to the percentage of the mass of each component to the total mass of the ibuprofen pharmaceutical composition; Formula 3: 3.00% ibuprofen, 2.00% xanthan gum, 8.75% microcrystalline cellulose-sodium carboxymethyl cellulose, 33.08% microcrystalline cellulose, 16.50% mannitol, 8.50% sodium carboxymethyl starch, 0.67% citric acid, 2.00% strawberry flavor and 0.50% aspartame, wherein the percentage refers to the percentage of the mass of each component to the total mass of the ibuprofen pharmaceutical composition; Formulation 4: 1.00% ibuprofen, 2.00% xanthan gum, 8.75% microcrystalline cellulose-sodium carboxymethyl cellulose, 33.08% microcrystalline cellulose, 16.50% mannitol, 8.50% sodium carboxymethyl starch, 0.67% citric acid, 2.00% strawberry flavor and 0.50% aspartame, wherein the percentage refers to the percentage of the mass of each component to the total mass of the ibuprofen pharmaceutical composition.

9. Use of the ibuprofen pharmaceutical composition according to any one of claims 1 to 8 in the preparation of a medicament for treating and / or alleviating mild to moderate pain diseases.

10. The method for preparing the ibuprofen pharmaceutical composition according to any one of claims 1 to 8, characterized in that: The preparation method comprises the following steps: mixing the components of the sustained-release pellets, wet granulating, preparing a soft material and then extruding and spheronizing to obtain the sustained-release pellets; mixing the components of the quick-release pellets, wet granulating, preparing a soft material and then extruding and spheronizing to obtain the quick-release pellets; and then mixing the sustained-release pellets and the quick-release pellets according to a proportion to obtain the ibuprofen pharmaceutical composition.

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