Loxoprofen sodium double-release capsule microtablet and preparation method thereof

Abstract

The invention provides a loxoprofen sodium double-release capsule micro-tablet and a preparation method of the loxoprofen sodium double-release capsule micro-tablet. Through the synergistic effect of the quick-release micro-tablet and the sustained-release micro-tablet, the quick-release micro-tablet can realize quick release and absorption, and the sustained-release micro-tablet can maintain relatively stable blood concentration for a long time. The administration frequency is reduced, the coordination of the postprandial administration requirement and the dietary habit is ensured, and the occurrence of gastrointestinal tract adverse reactions is reduced. The preparation provided by the invention conforms to the dosage form design of the hour pharmacology, can quickly take effect through administration twice every day, can maintain the blood concentration in the high-incidence time period of night diseases, avoids the disadvantage of taking medicine after meal when the night diseases attack, guarantees the sleep quality, and improves the overall treatment effect. The micro tablet is small in size and easy to swallow, and the medication compliance of patients with dysphagia is obviously improved. Through dosage form design and improvement, unmet clinical requirements are expected to be met by virtue of obvious advantages of the traditional Chinese medicine composition.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of capsules and micro-tablets, in particular to a losoxofen sodium double-release capsule micro-tablet and a preparation method thereof. BACKGROUND

[0002] Losoxofen sodium is a non-steroidal anti-inflammatory drug, which can reduce the production of prostaglandin by selectively inhibiting COX-1 and COX-2 enzymes. Prostaglandin is a key medium for causing human pain, inflammation and fever, so losoxofen sodium can effectively relieve related symptoms. Compared with similar drugs, it has the characteristic of fast onset. At present, domestic losoxofen sodium oral conventional release preparations include tablets, dispersible tablets, oral solutions, capsules and granules. In addition, there is also a losoxofen sodium gel patch.

[0003] However, although the oral conventional release preparation has a fast onset, it has a large blood concentration fluctuation, needs to be taken frequently, is easy to cause side effects, and has a short effective blood concentration maintenance time. If the patient needs to take the drug again after the onset of the disease at night, it will affect the sleep quality and treatment effect of the patient. Although the sustained-release tablets can maintain a relatively stable blood concentration and reduce the frequency of taking the drug, they have a slow onset and cannot meet the needs of patients who urgently need analgesia and anti-inflammatory. Therefore, there is an urgent need for a losoxofen sodium double-speed release preparation that meets the chronopharmacology dosage form design and eating habits, has a small number of drug taking times, can quickly take effect, and can maintain the blood concentration during the period of high incidence of diseases at night. SUMMARY

[0004] The present application provides a losoxofen sodium double-release capsule micro-tablet and a preparation method thereof to solve the above problems.

[0005] In a first aspect, the present application provides a losoxofen sodium double-release capsule micro-tablet, comprising: immediate-release micro-tablets and sustained-release micro-tablets filled into a capsule shell; wherein, The immediate-release micro-tablet comprises: an immediate-release micro-tablet core and a film coating layer wrapped on the surface of the immediate-release micro-tablet core, and the weight of the film coating layer is 5%-20% of the weight of the immediate-release micro-tablet core. The immediate-release micro-tablet core comprises, based on the total weight of each immediate-release micro-tablet core: 10%-45% of losoxofen sodium, 25%-75% of a filler, 0.5%-10% of a binder, 2%-20% of a disintegrant, 0.02%-5% of a glidant and 0.05%-5% of a lubricant; The sustained-release micro-tablet comprises: a sustained-release micro-tablet core and a coating layer wrapped on the surface of the sustained-release micro-tablet core, and the weight of the coating layer is 5%-40% of the weight of the sustained-release micro-tablet core. The sustained release microtablet core comprises, based on the total weight of the sustained release microtablet core: 10-50% of sodium loxoprofen, 5-45% of a filler, 10-70% of a release retardant, 0.05-10% of a binder, 0.02-5% of a glidant, and 0.05-5% of a lubricant.

[0006] 5-20% with respect to the weight of the film coating layer means any value in the range of 5% to 20%, such as, for example, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 15%, 16%, 18%, and 20%.

[0007] 10-45% with respect to the weight ratio of sodium loxoprofen in the immediate release microtablet means any value in the range of 10% to 45%, such as, for example, 10%, 12%, 14%, 15%, 16%, 18%, 20%, 22%, 24%, 26%, 28%, 30%, 32%, 34%, 36%, 38%, 40%, 42%, 44%, and 45%.

[0008] 25-75% with respect to the weight ratio of the filler in the immediate release microtablet means any value in the range of 25% to 75%, such as, for example, 25%, 27%, 30%, 32%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 72%, and 75%.

[0009] 0.5-10% with respect to the weight ratio of the binder in the immediate release microtablet means any value in the range of 0.5% to 10%, such as, for example, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, and 10%.

[0010] 2-20% with respect to the weight ratio of the disintegrant in the immediate release microtablet means any value in the range of 2% to 20%, such as, for example, 2%, 4%, 6%, 8%, 10%, 12%, 14%, 16%, 18%, and 20%.

[0011] 0.02-5% with respect to the weight ratio of the glidant in the immediate release microtablet means any value in the range of 0.02% to 5%, such as, for example, 0.02%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, and 5%.

[0012] 0.05-5% with respect to the weight ratio of the lubricant in the immediate release microtablet means any value in the range of 0.05% to 5%, such as, for example, 0.02%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, and 5%.

[0013] 10%-50% with respect to the weight ratio of the loxoprofen sodium in the sustained-release microtablets means any value in the range of 10% to 50%, such as, for example, 10%, 12%, 14%, 16%, 18%, 20%, 22%, 24%, 25%, 28%, 30%, 32%, 34%, 36%, 38%, 40%, 42%, 44%, 45%, 46%, 47%, 48%, and 50%.

[0014] 5%-45% with respect to the weight ratio of the filler in the sustained-release microtablets means any value in the range of 5% to 45%, such as, for example, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 42%, and 45%.

[0015] 10%-70% with respect to the weight ratio of the release retardant in the sustained-release microtablets means any value in the range of 10% to 70%, such as, for example, 10%, 20%, 30%, 40%, 50%, 60%, 65%, 68%, and 70%.

[0016] 0.05%-10% with respect to the weight ratio of the binder in the sustained-release microtablets means any value in the range of 0.05% to 10%, such as, for example, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, and 10%.

[0017] 0.02%-5% with respect to the weight ratio of the glidant in the sustained-release microtablets means any value in the range of 0.02% to 5%, such as, for example, 0.02%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1%, 2%, 3%, 4%, and 5%.

[0018] 0.05%-5% with respect to the weight ratio of the lubricant in the sustained-release microtablets means any value in the range of 0.05% to 5%, such as, for example, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1%, 2%, 3%, 4%, and 5%.

[0019] The content of the loxoprofen sodium in each of the immediate-release microtablets and each of the sustained-release microtablets is 0.5 mg to 5 mg.

[0020] 0.5 mg to 5 mg with respect to the content of the loxoprofen sodium in each of the immediate-release microtablets and each of the sustained-release microtablets means any value in the range of 0.5 mg to 5 mg, such as, for example, 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, and 5.0 mg.

[0021] 5%-40% refers to any value in the range of 5% to 40%, such as 5%, 10%, 15%, 20%, 25%, 30%, 35%, and 40%, with respect to the weight of the coating layer relative to the sustained-release microtablet core.

[0022] Preferably, The content of the sodium loxoprofen in each of the immediate-release microtablet is 1-3 mg.

[0023] The content of the sodium loxoprofen in each of the sustained-release microtablet is 1-3 mg.

[0024] 1-3 mg refers to any value in the range of 1 to 3 mg, such as 1 mg, 1.5 mg, 2 mg, 2.5 mg, and 3 mg, with respect to the content of the sodium loxoprofen in each of the immediate-release microtablet.

[0025] 1-3 mg refers to any value in the range of 1 to 3 mg, such as 1 mg, 1.5 mg, 2 mg, 2.5 mg, and 3 mg, with respect to the content of the sodium loxoprofen in each of the sustained-release microtablet.

[0026] Preferably, The diameter of the immediate-release microtablet and the sustained-release microtablet is 1-3 mm.

[0027] 1-3 mm refers to any value in the range of 1 to 3 mm, such as 1 mm, 1.5 mm, 2 mm, 2.5 mm, and 3 mm, with respect to the diameter of each of the immediate-release microtablet and the sustained-release microtablet.

[0028] Preferably, The coating layer includes an enteric coating layer, or a coating layer sequentially wrapped on the surface of the sustained-release microtablet core by an isolation coating layer and an enteric coating layer.

[0029] The coating layer of the sustained-release microtablet core can be only an enteric coating layer, or an enteric coating layer coated on the basis of the isolation coating layer coated on the sustained-release microtablet core.

[0030] Preferably, When the coating layer includes an enteric coating layer, the enteric coating layer accounts for 15%-40% of the weight of the sustained-release microtablet core.

[0031] 15%-40% refers to any value in the range of 15% to 40%, such as 15%, 20%, 25%, 30%, 35%, and 40%, with respect to the weight of the enteric coating layer.

[0032] It should be noted that when the coating layer is only an enteric coating layer, the weight of the enteric coating layer is 15%-40% of the weight of the sustained-release microtablet core.

[0033] Preferably, When the coating layer comprises the separation coating layer and the enteric coating layer, The weight percentage of the separation coating layer to the weight of the sustained-release microtablet core is 5%-20%; The weight percentage of the enteric coating layer to the total weight of the sustained-release microtablet core and the separation coating layer is 10%-30%.

[0034] Specifically, when the coating layer on the surface of the sustained-release microtablet core is composed of the separation coating layer and the enteric coating layer which are sequentially coated on the surface of the sustained-release microtablet core, the weight percentage of the separation coating layer to the weight of the sustained-release microtablet core is 5%-20%, which means any value within the range of 5% to 20%, such as 5%, 10%, 15%, and 20%. The weight percentage of the enteric coating layer to the weight of the sustained-release microtablet core is 10%-30%, which means any value within the range of 10% to 30%, such as 10%, 15%, 20%, 25%, and 30%.

[0035] Preferably, The enteric coating layer comprises at least one of methacrylic acid-ethyl acrylate copolymer, methacrylic acid-ethyl acrylate copolymer aqueous dispersion, acrylic resin, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, talc, triethyl citrate, sodium bicarbonate, colloidal silicon dioxide, Opadry®, and Acryl-EZE®.

[0036] Specifically, the enteric coating layer can be any of the above single substances, or a combination of two or more substances, but is not limited thereto.

[0037] For example, the enteric coating layer can be a mixture of methacrylic acid-ethyl acrylate copolymer, triethyl citrate, sodium bicarbonate, talc, and colloidal silicon dioxide. It can also be a mixture of methacrylic acid-ethyl acrylate copolymer aqueous dispersion, triethyl citrate, sodium bicarbonate, talc, and colloidal silicon dioxide.

[0038] It should be noted that Opadry® refers to commercially available Opadry series of stomach soluble film coating premix; Acryl-EZE® refers to commercially available Yakui series of enteric film coating premix.

[0039] Preferably, The color of the enteric coating layer of the sustained-release microtablet is different from the color of the film coating layer of the immediate-release microtablet.

[0040] Specifically, in order to distinguish the immediate-release microtablet and the sustained-release microtablet for the patient and in the production process, when the sustained-release microtablet has only an enteric coating layer, the enteric coating layer can be any other color different from the color of the film coating layer of the immediate-release microtablet; when the sustained-release microtablet has not only an isolation coating layer but also an enteric coating layer, the enteric coating layer can be any other color different from the color of the film coating layer of the immediate-release microtablet. For example, the color of the film coating layer of the immediate-release microtablet is yellow, and the color of the enteric coating layer of the sustained-release microtablet can be other colors except white, such as white.

[0041] Preferably, The filler in the immediate-release microtablet and the sustained-release microtablet comprises at least one of lactose, microcrystalline cellulose, corn starch, sucrose, pregelatinized starch, and mannitol.

[0042] Specifically, the filler of the immediate-release microtablet can be any of the above single substances or a combination of two or more, but is not limited thereto.

[0043] The filler of the sustained-release microtablet can be any of the above single substances or a combination of two or more, but is not limited thereto.

[0044] Preferably, The binder in the immediate-release microtablet and the sustained-release microtablet comprises at least one of povidone, starch paste, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and sodium carboxymethyl cellulose.

[0045] Specifically, the binder of the immediate-release microtablet can be any of the above single substances or a combination of two or more, but is not limited thereto.

[0046] The binder of the sustained-release microtablet can be any of the above single substances or a combination of two or more, but is not limited thereto.

[0047] Preferably, The lubricant in the immediate-release microtablet and the sustained-release microtablet comprises at least one of magnesium stearate, talc, sodium stearyl fumarate, calcium stearate, and stearic acid.

[0048] Specifically, the lubricant of the immediate-release microtablet can be any of the above single substances or a combination of two or more, but is not limited thereto.

[0049] The lubricant of the sustained-release microtablet can be any of the above single substances or a combination of two or more, but is not limited thereto.

[0050] Preferably, The glidant in the immediate-release microtablet and the sustained-release microtablet comprises at least one of talc, colloidal silicon dioxide, and silicon dioxide.

[0051] Specifically, the glidant of the immediate-release microtablet can be any of the above single substances, or a combination of two or more, but is not limited thereto.

[0052] The release retardant of the sustained-release microtablet can be any of the above single substances, or a combination of two or more, but is not limited thereto.

[0053] Preferably, The disintegrant in the immediate-release microtablet includes at least one of corn starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked povidone, and cross-linked sodium carboxymethyl cellulose.

[0054] Specifically, the disintegrant in the immediate-release microtablet can be any of the above single substances, or a combination of two or more, but is not limited thereto.

[0055] Preferably, The release retardant in the sustained-release microtablet includes at least one of hypromellose, hydroxypropyl cellulose, carbomer, sodium carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, and methyl cellulose.

[0056] Specifically, the release retardant in the sustained-release microtablet can be hypromellose, or hydroxypropyl cellulose, or sodium carboxymethyl cellulose, or a combination of multiple components, such as a combination of hypromellose and ethyl cellulose, but is not limited thereto.

[0057] Preferably, The film coating layer includes a mixture of hypromellose, hydroxypropyl cellulose, and talc, or Opadry®.

[0058] It should be noted that when the film coating layer is Opadry®, Opadry® refers to commercially available Opadry series of gastric soluble film coating premixes. In addition, the film coating layer of the present application can also be a film coating premix obtained by mixing hypromellose, hydroxypropyl cellulose, and talc.

[0059] Preferably, When the release retardant in the sustained-release microtablet is hypromellose, the weight ratio of the hypromellose is 10%-55%.

[0060] When the release retardant in the sustained-release microtablet is hypromellose, 10%-55% with respect to the weight ratio of the hypromellose means any value within the range of 10% to 55%, such as 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, and 55%.

[0061] Specifically, the hypromellose of the present application can be hypromellose K4M or hypromellose K100M. The release retardant of the present application can be only hypromellose K4M or only hypromellose K100M, or a mixture consisting of hypromellose K4M and hypromellose K100M.

[0062] When the release retardant in the sustained-release microtablet comprises hypromellose K4M and hypromellose K100M, the weight ratio of hypromellose K4M is 10%-55% and the weight ratio of hypromellose K100M is 10%-55%. The weight ratio of hypromellose K4M of 10%-50% means any value within the range of 10% to 50%, such as 10%, 15%, 20%, 25%, 26%, 28%, 29%, 30%, 32%, 34%, 35%, 36%, 38%, 39%, 40%, 42%, 44%, 45%, 46%, 48%, 49%, and 50%. The weight ratio of hypromellose K100M of 10%-50% means any value within the range of 10% to 50%, such as 10%, 15%, 20%, 25%, 26%, 28%, 29%, 30%, 32%, 34%, 35%, 36%, 38%, 39%, 40%, 42%, 44%, 45%, 46%, 48%, 49%, 50%, and 55%.

[0063] Preferably, When the filler in the immediate-release microtablet is lactose and microcrystalline cellulose, the weight ratio of lactose is 25%-50% and the weight ratio of microcrystalline cellulose is 7%-32%.

[0064] When the filler in the immediate-release microtablet is lactose and microcrystalline cellulose, 25%-50% in terms of the weight ratio of lactose means any value within the range of 25% to 50%, such as 25%, 26%, 28%, 29%, 30%, 32%, 34%, 35%, 36%, 38%, 39%, 40%, 42%, 44%, 45%, 46%, 48%, 49%, and 50%.

[0065] When the filler in the immediate-release microtablet is lactose and microcrystalline cellulose, 7%-32% in terms of the weight ratio of microcrystalline cellulose means any value within the range of 7% to 32%, such as 7%, 8%, 10%, 12%, 14%, 15%, 16%, 18%, 20%, 22%, 24%, 25%, 26%, 28%, 30%, and 32%.

[0066] Preferably, The ratio of the total amount of sodium loxoprofen in the immediate-release microtablet to the total amount of sodium loxoprofen in the sustained-release microtablet in each capsule is 1:(0.8-3.5).

[0067] The total content of sodium loxoprofen in the immediate-release microtablets and the sustained-release microtablets in each capsule is 90 mg.

[0068] It should be noted that if the total content of sodium loxoprofen in the immediate-release microtablets and the sustained-release microtablets in each capsule is 90 mg, and the ratio of the total amount of sodium loxoprofen in the immediate-release microtablets to the total amount of sodium loxoprofen in the sustained-release microtablets is 1:(0.8-3.5), it indicates that in each capsule: If the total content of sodium loxoprofen in all immediate-release microtablets is 50 mg, the total content of sodium loxoprofen in all sustained-release microtablets is 40 mg; If the total content of sodium loxoprofen in all immediate-release microtablets is 45 mg, the total content of sodium loxoprofen in all sustained-release microtablets is 45 mg; If the total content of sodium loxoprofen in all immediate-release microtablets is 40 mg, the total content of sodium loxoprofen in all sustained-release microtablets is 50 mg; If the total content of sodium loxoprofen in all immediate-release microtablets is 35 mg, the total content of sodium loxoprofen in all sustained-release microtablets is 55 mg; If the total content of sodium loxoprofen in all immediate-release microtablets is 30 mg, the total content of sodium loxoprofen in all sustained-release microtablets is 60 mg; If the total content of sodium loxoprofen in all immediate-release microtablets is 20 mg, the total content of sodium loxoprofen in all sustained-release microtablets is 70 mg.

[0069] In a second aspect, the application provides a preparation method of the sodium loxoprofen dual-release capsule microtablets according to any one of the first aspect, comprising: The immediate-release microtablets are prepared by the following method: Mix the prescription amount of sodium loxoprofen with the filler, the binder and the disintegrant, and then add the ethanol aqueous solution and mix to obtain the soft material of the immediate-release microtablets; Screen the soft material of the immediate-release microtablets to obtain the wet granules of the immediate-release microtablets; Dry and screen the wet granules of the immediate-release microtablets to obtain the dry granules of the immediate-release microtablets; Mix the dry granules of the immediate-release microtablets with the glidant and the lubricant, and then perform the tabletting operation to obtain the tablet cores of the immediate-release microtablets; Prepare the film coating liquid, and use the film coating liquid to coat the tablet cores of the immediate-release microtablets to obtain the immediate-release microtablets with the film coating layer wrapped on the tablet cores of the immediate-release microtablets; The sustained-release microtablets are prepared by the following method: Mix the prescription amount of sodium loxoprofen with the filler and the release retardant, and then add the binder and the ethanol aqueous solution and mix to obtain the soft material of the sustained-release microtablets; The soft material of the sustained-release micro-tablets is sieved to obtain wet granules of the sustained-release micro-tablets; The wet granules of the sustained-release micro-tablets are dried and sieved to obtain dry granules of the sustained-release micro-tablets; The dry granules of the sustained-release micro-tablets are mixed with a glidant and a lubricant, and subjected to a tabletting operation to obtain sustained-release micro-tablet cores; A coating liquid is prepared, and the sustained-release micro-tablet cores are coated with the coating liquid to obtain sustained-release micro-tablets with a coating layer wrapped on the sustained-release micro-tablet cores; The immediate-release micro-tablets and the sustained-release micro-tablets are filled into a capsule shell.

[0070] It should be noted that the aqueous ethanol solution used in the preparation of the immediate-release micro-tablets can be an aqueous ethanol solution containing 30%-70% ethanol. For example, an aqueous ethanol solution containing 30% ethanol, an aqueous ethanol solution containing 40% ethanol, an aqueous ethanol solution containing 50% ethanol, an aqueous ethanol solution containing 55% ethanol, an aqueous ethanol solution containing 60% ethanol, and an aqueous ethanol solution containing 70% ethanol.

[0071] The aqueous ethanol solution used in the preparation of the sustained-release micro-tablets can be an aqueous ethanol solution containing 60%-95% ethanol. For example, an aqueous ethanol solution containing 60% ethanol, an aqueous ethanol solution containing 70% ethanol, an aqueous ethanol solution containing 80% ethanol, an aqueous ethanol solution containing 90% ethanol, and an aqueous ethanol solution containing 95% ethanol.

[0072] The present application provides a losoxofen sodium double-release capsule micro-tablet and a preparation method thereof. The losoxofen sodium double-release capsule micro-tablet comprises immediate-release micro-tablets and sustained-release micro-tablets filled into a capsule shell. Through the synergistic effect of the immediate-release micro-tablets and the sustained-release micro-tablets of the present application, the immediate-release micro-tablets can achieve rapid release and absorption, rapidly reach an effective blood drug concentration, and then cooperate with the sustained-release micro-tablets to maintain a relatively stable blood drug concentration for a long time, achieving rapid onset and long-term maintenance of therapeutic effect and reducing gastrointestinal adverse reactions. This combination not only reduces the number of administrations, but also is more convenient to coordinate with the postprandial administration of losoxofen sodium and daily dietary habits, thereby further reducing the occurrence of gastrointestinal adverse reactions. In addition, the losoxofen sodium double-release capsule micro-tablet of the present application conforms to the design of chronopharmacology dosage forms, and through twice daily administration, it can not only exert a rapid onset effect, but also maintain an effective blood drug concentration during the period of high incidence of diseases at night, avoiding the disadvantages of postprandial administration at night when diseases occur and ensuring the sleep quality of patients, thereby improving the overall treatment effect. Moreover, the immediate-release micro-tablets and the sustained-release micro-tablets of the present application are small in size and easy to swallow, significantly improving the medication compliance of patients with dysphagia. Through the design and improvement of the dosage form, the present application has obvious advantages, so as to meet the unmet clinical needs. BRIEF DESCRIPTION OF DRAWINGS

[0073] Figure 1 Table 1 is the test results of various prescriptions provided in Example 1 of the present application; Figure 2is the adhesive investigation result provided in Embodiment 2 of the present application; Figure 3 is the flow aid investigation result provided in Embodiment 3 of the present application; Figure 4 is the lubricant investigation result provided in Embodiment 4 of the present application; Figure 5 is the release retardant investigation result provided in Embodiment 5 of the present application; Figure 6 is the disintegrant investigation result provided in Embodiment 6 of the present application; Figure 7 is the filler investigation result provided in Embodiment 7 of the present application; Figure 8 is the capsule shell influence on immediate-release microtablets and sustained-release microtablets investigation result provided in Embodiment 8 of the present application; Figure 9 is a pharmacokinetic-time curve diagram provided in Embodiment 9 of the present application; Figure 10 is another pharmacokinetic-time curve diagram provided in Embodiment 9 of the present application. DETAILED DESCRIPTION

[0074] In order to make the objects, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application will be described clearly and completely below with reference to the drawings in the embodiments of the present application. Obviously, the described embodiments are some but not all of the embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by a person of ordinary skill in the art without creative work fall within the protection scope of the present application.

[0075] Loxoprofen sodium is a non-steroidal anti-inflammatory drug (NSAID) that reduces the production of prostaglandins by selectively inhibiting cyclooxygenase (COX-1 and COX-2). Prostaglandins are important mediators of pain, inflammation and fever in the human body, so loxoprofen sodium can effectively relieve related symptoms. Compared with similar drugs, loxoprofen sodium has the characteristics of rapid onset, which makes it widely used in clinical practice.

[0076] At present, the loxoprofen sodium oral immediate-release preparations approved for marketing include loxoprofen sodium tablets, loxoprofen sodium dispersible tablets, loxoprofen sodium oral solution, loxoprofen sodium capsules and loxoprofen sodium granules.

[0077] For the conventional tablet, the dosage of loxoprofen sodium tablet is 60 mg (marketed formulation of Example 9 of the present application), and the indications include: ① anti-inflammatory analgesic for rheumatoid arthritis, osteoarthritis, lumbar spondylosis, shoulder periarthritis, cervical shoulder wrist syndrome, toothache, and the like; ② analgesic and anti-inflammatory after surgery, after trauma, and after tooth extraction; ③ antipyretic and analgesic for acute upper respiratory tract inflammation (including acute upper respiratory tract inflammation with acute bronchitis). Adults usually take 60 mg (1 tablet) orally at a time, three times a day, and the specific dosage can be appropriately adjusted according to age and symptoms, but the maximum daily dose is not more than 180 mg. The drug should be taken with meals, and it is not suitable to be taken on an empty stomach. Common adverse reactions include digestive system symptoms (such as stomach discomfort, abdominal pain, nausea, vomiting, loss of appetite, etc., with an incidence of about 2.25%), edema and dropsy (0.59%), skin rash and urticaria (0.21%), and drowsiness (0.10%). Although it has a fast onset, it has a large fluctuation in blood drug concentration, needs to be taken frequently, is prone to cause side effects, and has a short maintenance time of effective blood drug concentration. If the drug needs to be taken again at night after the onset of disease at night, it will affect the sleep quality and treatment effect of the patient.

[0078] The topical treatment loxoprofen sodium gel patch has indications for osteoarthritis, muscle pain, and swelling or pain caused by trauma. It is used once a day and is applied to the affected area. The main adverse reactions are local skin reactions, such as itching (2.1%), erythema (1.5%), contact dermatitis (1.4%), and the like, and digestive tract discomfort (such as stomach discomfort, 0.6%). According to the monitoring data after listing in Japan, the incidence of adverse reactions of loxoprofen sodium gel is 2.9%. It can maintain long-term local treatment, but it cannot meet the treatment needs of toothache, postoperative or post-extraction, acute upper respiratory tract inflammation, and the like; although it is a topical treatment external drug, it also has digestive tract adverse reactions, and increases local skin adverse reactions.

[0079] The loxoprofen sodium preparation listed in Korea has a sustained-release effect in the tablet core (40 mg), an enteric coating layer, and a rapid-release layer (50 mg) in the outer layer. According to literature, the peak concentration of this sustained-release tablet is 30% higher than that of the ordinary tablet. However, long-term medication may increase the risk of side effects, and if a patient mistakenly chews it, it may cause “burst release”, thereby affecting the efficacy and safety risk. In addition, the production process of loxoprofen sodium controlled-release tablets is relatively complex, and the industrialization is relatively difficult. Moreover, there is a risk of patients mistakenly chewing controlled-release tablets, which can destroy the structure of the sustained-release layer, possibly leading to uneven drug release and early release, increasing the risk of “burst release”, and it is difficult to flexibly adjust the dosage according to the actual needs of different patients such as age and symptoms. For loxoprofen sodium oral sustained-release preparations, the onset time is slower, and the anti-inflammatory and analgesic effects are also delayed, which cannot meet the treatment needs of patients in urgent need of analgesia and anti-inflammatory.

[0080] To further improve the comprehensive treatment effect of patients and protect the quality of sleep, the loxoprofen sodium double-release capsule-in-microtablets of the present application emerges as the times require. The loxoprofen sodium double-release capsule-in-microtablets of the present application combines the dual-module design of immediate release and delayed release. The first dose is rapidly released within 15 minutes, quickly relieving acute pain and anti-inflammatory; the slow-release part can maintain a long time of blood drug concentration, reducing the daily medication frequency relative to the oral conventional release preparation, and significantly improving patient compliance. This design is not only suitable for acute patients' emergency anti-inflammatory analgesia, but also suitable for long-term maintenance therapy of chronic patients, and suitable for patients who need systemic treatment. The double-release capsule-in-microtablets of the present application, through the combination of rapid-release and slow-release microtablets, the release speed of the rapid-release part is faster, and the rapid-release dose is appropriately reduced, thereby reducing the fluctuation of blood drug concentration; the slow-release microtablets can be released continuously and slowly, maintaining a stable blood drug concentration. Since loxoprofen sodium needs to be administered after meals, this design can quickly reach the effective concentration and reduce the inconvenience of frequent medication, and the design also takes into account the eating habits of patients, and the designed medication interval is more reasonable, which can reduce the impact of postprandial medication on patients' eating habits, and can reduce adverse reactions, especially in the time period of high incidence of night diseases, maintaining a relatively stable blood drug concentration, improving the treatment effect, and effectively avoiding the decline in sleep quality and eating inconvenience caused by patients' night "pain wake-up" and the need for postprandial medication at night. In addition, since the dosage of loxoprofen sodium preparation can be flexibly increased or decreased according to the age and symptoms of patients, the present application distinguishes the rapid-release microtablets and the slow-release microtablets by color, so that patients can conveniently manually measure or accurately control the dosage using a counter, and can flexibly adjust the accurate dosage according to the age and symptoms to meet the clinical treatment needs. The design of capsule-in-microtablets also takes into account patients with difficulty swallowing, and directly taking microtablets can effectively improve medication compliance. In addition, compared with the marketed topical loxoprofen sodium gel patch, the present preparation has a wider indication, such as the treatment of toothache, postoperative or post-extraction, acute upper respiratory tract inflammation, etc., and solves the compliance problem of oral tablets. It not only solves the problem of insufficient compliance of loxoprofen sodium tablets (marketed preparation of Example 9 of the present application) in three times of medication in a day, but also avoids the problems of swallowing difficulty and postprandial medication coordination, especially can provide a relatively stable blood drug concentration during the night, thereby effectively relieving night symptoms and ensuring the sleep quality of patients. In addition, the loxoprofen sodium double-release capsule-in-microtablets of the present application have a faster onset speed compared with loxoprofen sodium sustained-release tablets, and avoid the skin adverse reactions that may occur when using loxoprofen sodium gel patches, such as itching, erythema and contact dermatitis, etc. The loxoprofen sodium double-release capsule-in-microtablets of the present application not only retain the wide indications of oral preparations, but also solve many problems of common tablets, such as frequent medication, inconvenient dosage adjustment, high adverse reactions, and impact on patients' sleep quality, etc. Through the design and improvement of the dosage form, with its obvious advantages, it is expected to meet the unmet clinical needs.

[0081] The application will be further described in connection with specific examples.

[0082] Example 1: Prescription information Table 1 is the prescription information of the present application (expressed in weight %), and the specific information is as follows: Table 1 Prescription information

[0083] (1) The preparation method of the immediate-release microtablets and the sustained-release microtablets of the above-mentioned prescription 1 to prescription 7 is as follows: 1) The immediate-release microtablets are prepared by the following method: The prescription amount of loxoprofen sodium is uniformly mixed with lactose, microcrystalline cellulose, povidone K30, and sodium carboxymethyl starch; and 50% ethanol aqueous solution is added and uniformly mixed to prepare a soft material of the immediate-release microtablets; The soft material of the immediate-release microtablets is sieved to prepare wet granules of the immediate-release microtablets; The wet granules of the immediate-release microtablets are dried and sieved to prepare dry granules of the immediate-release microtablets; The dry granules of the immediate-release microtablets are uniformly mixed with silicon dioxide and magnesium stearate, and tabletting operation is performed using a circular deep concave punch die to prepare a tablet core of the immediate-release microtablets; A film coating liquid as a film coating layer is prepared, and the tablet core of the immediate-release microtablets is coated using the film coating liquid, and the coating weight gain of the film coating layer is controlled at 5%-20% to obtain the immediate-release microtablets.

[0084] 2) The sustained-release microtablets are prepared by the following method: The prescription amount of loxoprofen sodium is uniformly mixed with microcrystalline cellulose, hydroxypropyl methyl cellulose K4M, and hydroxypropyl methyl cellulose K100M, and povidone K30 and ethanol aqueous solution are added and uniformly mixed to prepare a soft material of the sustained-release microtablets; The soft material of the sustained-release microtablets is sieved to prepare wet granules of the sustained-release microtablets; The wet granules of the sustained-release microtablets are dried and sieved to prepare dry granules of the sustained-release microtablets; The dry granules of the sustained-release microtablets are uniformly mixed with silicon dioxide and magnesium stearate, and tabletting operation is performed using a circular deep concave punch die to prepare a tablet core of the sustained-release microtablets; An isolation layer coating liquid as an isolation coating layer and an enteric layer coating liquid as an enteric coating layer are prepared, the tablet core of the sustained-release microtablets is coated using the isolation layer coating liquid, and the coating weight gain of the isolation coating layer is controlled at 5%-20%, the tablet core of the sustained-release microtablets with the isolation coating layer is coated using the enteric layer coating liquid, and the coating weight gain of the enteric coating layer is controlled at 10%-30% to obtain the sustained-release microtablets; The immediate-release microtablets and the sustained-release microtablets are filled into a capsule shell.

[0085] (2) The amount of sodium loxoprofen in each tablet of the immediate-release microtablets and the sustained-release microtablets in prescription 1, prescription 3, prescription 5, prescription 6 and prescription 7 in Table 1 is 2.276 mg in terms of sodium loxoprofen dihydrate; the amount of sodium loxoprofen in each tablet of the immediate-release microtablets and the sustained-release microtablets in prescription 2 is 3.414 mg in terms of sodium loxoprofen dihydrate; and the amount of sodium loxoprofen in each tablet of the immediate-release microtablets and the sustained-release microtablets in prescription 4 is 1.138 mg in terms of sodium loxoprofen dihydrate. The diameter of the circular deep concave die can be 1 mm, 2 mm or 3 mm.

[0086] (3) Dissolution test results The dissolution of the immediate-release microtablets, the sustained-release microtablets, and the immediate-release microtablets and the sustained-release microtablets as a complete prescription in prescription 1 to prescription 7 is investigated in terms of dissolution.

[0087] The dissolution of the immediate-release microtablets in prescription 1-1 to prescription 7-1 reaches more than 85% at 15 min, meeting the requirement of very fast dissolution and the requirement of fast release at 15 min. The dissolution of the sustained-release microtablets in prescription 1-2 to prescription 7-2 reaches 12% to 19% at 1 h, prescription 6-2 releases relatively fastest, and prescription 1-2 releases relatively mildly. The dissolution of the sustained-release microtablets in prescription 1-2 to prescription 7-2 reaches more than 60% at 6 h and is not less than 95% at 12 h, meeting the requirement of sustained-release dissolution.

[0088] Figure 1 The dissolution curves of prescription 1 to prescription 7 are shown in FIG. 1, in which the horizontal axis represents time and the vertical axis represents dissolution. Figure 1 It can be seen that the dissolution of each prescription reaches more than 20% at 15 min. The release rates of the subsequent prescriptions are different, but the dissolution of each prescription reaches 80% at 8 h and more than 95% at 12 h. This indicates that each prescription can release the drug fast in a short time and can continuously release the drug in a long time, maintaining a relatively stable blood drug concentration.

[0089] It should be noted that each complete prescription in the present application is composed of the immediate-release microtablets and the sustained-release microtablets, for example, prescription 1 is composed of prescription 1-1 of the immediate-release microtablets and prescription 1-2 of the sustained-release microtablets. Prescription 2 is composed of prescription 2-1 of the immediate-release microtablets and prescription 2-2 of the sustained-release microtablets. The compositions of the remaining prescriptions in the present embodiment are the same as this case, and will not be described herein again.

[0090] It should be noted that the amount of sodium loxoprofen in each embodiment of the present application is in terms of sodium loxoprofen dihydrate.

[0091] Example 2: Investigation of the Binder The present example is based on the prescription 3 in example 1, with prescription 3 as a comparative prescription, to investigate the influence of the type and amount of adhesive on the dissolution of the immediate-release microtablets and the sustained-release microtablets.

[0092] Table 2 Adhesive investigation summary of immediate-release microtablets and sustained-release microtablets

[0093] The preparation method of each prescription sample in Table 2 is the same as the preparation principle of the prescription 3 sample, which will not be repeated here.

[0094] For the adhesive, based on prescription 3, the present application also investigates methyl cellulose, hypromellose, sodium carboxymethyl cellulose, and investigates the amount of povidone K30. With dissolution as the investigation index, the dissolution of prescription 3111-1 to prescription 3115-1 of the immediate-release microtablets, the sustained-release microtablets, and the immediate-release microtablets and the sustained-release microtablets as a complete prescription is investigated.

[0095] The dissolution of prescription 3111-1 to prescription 3115-1 of the immediate-release microtablets is all above 85% at 15 min, showing the characteristics of rapid release of drugs. The dissolution of prescription 3111-2 to prescription 3115-2 of the sustained-release microtablets is 14%-20% at 1 h, all above 60% at 6 h, and all not less than 90% at 12 h, meeting the requirements of sustained-release dissolution.

[0096] Figure 2 The dissolution curves of each prescription in Table 2 are shown in the following figures. The horizontal coordinate is time, and the vertical coordinate is dissolution. Figure 2 It can be seen that the dissolution of prescription 3111 to prescription 3113 is all not less than 30% at 15 min, can reach above 85% at 8 h, and is all not less than 95% at 12 h. It can be seen that for the immediate-release microtablets and the sustained-release microtablets, under the same amount of povidone K30 and the same preparation method, using methyl cellulose, hypromellose, or sodium carboxymethyl cellulose to replace povidone K30 all meet the requirements of rapid release of drugs in the early stage and slow release of drugs in the later stage.

[0097] In addition, when the amount of povidone K30 in the immediate-release microtablets is 0.50% and the amount of povidone K30 in the sustained-release microtablets is 0.06%, the dissolution rate of prescription 3114 is basically the same as that of prescription 3, indicating that the amount of povidone K30 has little effect on the dissolution of prescription 3114. When the amount of povidone K30 in the immediate-release microtablets is 9.97% and the amount of povidone K30 in the sustained-release microtablets is 10.0%, the dissolution rate of prescription 3115 is basically the same as that of prescription 3, indicating that the amount of povidone K30 has little effect on the dissolution of prescription 3115. Therefore, both prescriptions meet the requirements of rapid release and slow release.

[0098] It should be noted that each complete prescription of the present application is composed of immediate-release microtablets and sustained-release microtablets, for example, prescription 3111 is composed of prescription 3111-1 of immediate-release microtablets and prescription 3111-2 of sustained-release microtablets. The composition of the remaining prescriptions in this example is the same as this case, and will not be repeated here.

[0099] Example 3: Investigation of flow aids This example is based on prescription 3 in Example 1, with prescription 3 as a comparative prescription, to investigate the effect of the type and amount of flow aids for immediate-release microtablets and sustained-release microtablets on dissolution.

[0100] Table 3 Summary of flow aid investigation of immediate-release microtablets and sustained-release microtablets

[0101] The preparation method of each prescription sample in Table 3 is the same as the preparation principle of prescription 3 sample, and will not be repeated here.

[0102] For flow aids, based on prescription 3, the present application also investigates talc, colloidal silicon dioxide, and the amount of silicon dioxide. With dissolution as the investigation index, the dissolution of prescription 3121 to prescription 3124 of immediate-release microtablets, sustained-release microtablets, and immediate-release microtablets and sustained-release microtablets as a complete prescription is investigated.

[0103] Prescription 3121-1 to prescription 3124-1 of immediate-release microtablets, the dissolution at 15 min is not less than 90%, meeting the requirement of very fast dissolution. Prescription 3121-2 to prescription 3124-2 of sustained-release microtablets, the dissolution at 1 h is not less than 10%, the dissolution at 6 h can reach 65%, and the dissolution at 12 h is not less than 90%, meeting the requirement of sustained-release dissolution.

[0104] Figure 3 For the dissolution curves of each prescription in Table 3, the horizontal coordinate is time, and the vertical coordinate is dissolution. From Figure 3 It can be seen that the dissolution of prescription 3121 and prescription 3122 at 15 min is 31%-32%, and the degree of rapid drug release in a short time is basically the same; the dissolution at 8 h can reach 85%, and the dissolution at 12 h is not less than 95%. It can be seen that for immediate-release microtablets and sustained-release microtablets, under the same amount of silicon dioxide and the same preparation method, using talc or colloidal silicon dioxide instead of silicon dioxide still meets the requirements of the present application for rapid release of drugs in a short time and subsequent slow release of drugs.

[0105] In addition, when the amount of silicon dioxide in the immediate-release microtablets and the sustained-release microtablets is 0.03%, the dissolution rate of the prescription 3123 is basically the same as that of the prescription 3, indicating that the amount of silicon dioxide in the prescription has little effect on the dissolution of the prescription 3123. When the amount of silicon dioxide in the immediate-release microtablets is 4.92% and the amount of silicon dioxide in the sustained-release microtablets is 5.00%, the dissolution rate of the prescription 3115 is basically the same as that of the prescription 3, indicating that the amount of silicon dioxide in the prescription also has little effect on the dissolution of the prescription 3124. In summary, both the prescriptions meet the requirements of fast release and slow release.

[0106] It should be noted that each complete prescription in the present application is composed of immediate-release microtablets and sustained-release microtablets, for example, the prescription 3121 is composed of the prescription 3121-1 for the immediate-release microtablets and the prescription 3121-2 for the sustained-release microtablets. The composition of the remaining prescriptions in the present example is the same as this case, which will not be described here.

[0107] Example 4: Lubricant investigation In the present example, the effects of the types and amounts of lubricants for the immediate-release microtablets and the sustained-release microtablets on the dissolution are investigated based on the prescription 3 in Example 1, with the prescription 3 as a comparative prescription.

[0108] Table 4: Lubricant investigation summary of immediate-release microtablets and sustained-release microtablets

[0109] The preparation methods of the sample of each prescription in Table 4 are the same as the preparation principle of the sample of the prescription 3, which will not be described here.

[0110] For the lubricants, the present application also investigates talc, sodium stearyl fumarate, calcium stearate, and the amount of magnesium stearate. The dissolution of the immediate-release microtablets, the sustained-release microtablets, and the immediate-release microtablets and the sustained-release microtablets as a complete prescription of the prescriptions 3131 to 3135 is investigated with the dissolution as the investigation index.

[0111] The dissolution of the prescriptions 3131-1 to 3135-1 for the immediate-release microtablets is not less than 85% at 15 min, meeting the requirement of very fast dissolution. The dissolution of the prescriptions 3131-1-3135-2 is not less than 10% at 1 h, not less than 65% at 6 h, and more than 90% at 12 h, meeting the requirement of slow release dissolution.

[0112] Figure 4 The dissolution curves of the prescriptions in Table 4 are shown in FIG. 4, in which the horizontal coordinate is time and the vertical coordinate is dissolution. From FIG. 4, it can be seen that the dissolution of the immediate-release microtablets is very fast, and the dissolution of the sustained-release microtablets is slow. Figure 4It can be seen that the dissolution of the three prescriptions is basically consistent in a short time, and the dissolution is not less than 85% at 8h and can reach 95% at 12h. It can be seen that, under the condition of the same amount of magnesium stearate and the same preparation method, the use of talc, sodium stearyl fumarate or calcium stearate to replace magnesium stearate can meet the requirements of the present application for the rapid release of drugs in the early stage and the slow release of drugs in the later stage.

[0113] In addition, when the amount of magnesium stearate in the immediate-release microtablets is 0.05% and the amount of magnesium stearate in the sustained-release microtablets is 0.06%, the dissolution rate of prescription 3134 is basically consistent with that of prescription 3, indicating that the amount of magnesium stearate in the prescription has little effect on the dissolution of prescription 3134. When the amount of magnesium stearate in the immediate-release microtablets is 4.92% and the amount of magnesium stearate in the sustained-release microtablets is 5.00%, the dissolution rate of prescription 3135 is basically consistent with that of prescription 3, indicating that the amount of magnesium stearate in the prescription also has little effect on the dissolution of prescription 3135. In summary, both prescriptions meet the requirements of rapid release and slow release.

[0114] It should be noted that each complete prescription of the present application is composed of immediate-release microtablets and sustained-release microtablets, for example, prescription 3131 is composed of prescription 3131-1 for immediate-release microtablets and prescription 3131-2 for sustained-release microtablets. The composition of the remaining prescriptions in this example is the same as this case, and will not be described here.

[0115] Example 5: Investigation of release retardant This example is based on prescription 3 in Example 1, with prescription 3 as a comparative prescription, to investigate the effect of the type and amount of release retardant in the sustained-release microtablets on the dissolution.

[0116] Table 5: Investigation of release retardant of sustained-release microtablets

[0117] The preparation method of each prescription sample in Table 5 is the same as the preparation principle of the prescription 3 sample, and will not be described here.

[0118] For the release retardant in the sustained-release microtablets, the present application also investigates sodium carboxymethyl cellulose and the amount of hydroxypropyl methyl cellulose (K4M) and hydroxypropyl methyl cellulose (K100M) based on prescription 3. The dissolution of the sustained-release microtablets of prescription 3141 to prescription 3145 is investigated with dissolution as the index. The immediate-release microtablets of prescription 3141 to prescription 3145 have the same prescription as the immediate-release microtablets of prescription 3.

[0119] The sustained-release microtablet formulations 3144-1 and 3145-1 showed a dissolution rate of 25%-30% at 1 hour, 70%-75% at 6 hours, and over 95% at 12 hours. Compared to formulations 3-2, 3141-1, and 3142-1, formulations 3144-1 and 3145-1 had relatively faster release rates, but still met the requirements for sustained release. Formulation 3143-1 achieved a dissolution rate of 35% at 1 hour and 78% at 6 hours. While its release rate was relatively fast and its sustained-release effect was relatively weaker, it still met the requirements for sustained release.

[0120] Figure 5 Table 5 shows the dissolution curves for each formulation, with time on the x-axis and dissolution rate on the y-axis. From... Figure 5 It can be seen that all formulations achieved dissolution rates above 30% at 15 minutes. Formulations 3141, 3142, 3144, and 3145 all achieved dissolution rates above 80% at 8 hours and above 95% at 12 hours, with relatively gradual dissolution rates consistent with formulation 3. While formulation 3143 achieved immediate release at 15 minutes, its release rate was relatively fast, reaching 90% at 8 hours. Compared to formulation 3, the sustained-release effect of formulation 3143 was relatively weaker, but it still met the requirements for sustained release. In summary, using sodium carboxymethyl cellulose instead of hydroxypropyl methylcellulose (K4M and K100M), and adjusting the dosage within the range of release inhibitor dosages, both meet the requirements of this application for rapid drug release in the short term and subsequent slow drug release.

[0121] It should be noted that each complete prescription in this application consists of immediate-release microtablets and sustained-release microtablets. Prescription 3141 consists of prescription 3-1 of immediate-release microtablets and prescription 3141-1 of sustained-release microtablets. Prescription 3142 consists of prescription 3-1 of immediate-release microtablets and prescription 3142-1 of sustained-release microtablets. Prescription 3143 consists of prescription 3-1 of immediate-release microtablets and prescription 3143-1 of sustained-release microtablets. Prescription 3144 consists of prescription 3-1 of immediate-release microtablets and prescription 3144-1 of sustained-release microtablets. Prescription 3145 consists of prescription 3-1 of immediate-release microtablets and prescription 3145-1 of sustained-release microtablets.

[0122] Example 6: Disintegrant Investigation Based on formulation 3 in Example 1, this embodiment uses formulation 3 as a comparative formulation to investigate the effect of the type and dosage of immediate-release microplates on dissolution.

[0123] Table 6 Summary of the investigation of disintegrants for immediate-release microtablets

[0124] The preparation methods for each prescription sample in Table 6 are the same as those for prescription sample 3, and will not be repeated here.

[0125] For the disintegrant in the immediate-release microtablets, corn starch, low-substituted hydroxypropyl cellulose, cross-linked povidone were also investigated based on Formulation 3, and the amount of sodium starch glycolate was also investigated. The dissolution of Formulations 3151 to 3155 was investigated with dissolution as the index, wherein Formulations 3151 to 3155 were the same as Formulation 3. The dissolution of Formulations 3151 to 3155 as immediate-release microtablets, as sustained-release microtablets, and as complete formulations was investigated with dissolution as the index.

[0126] Formulations 3151-1 to 3155-1, the dissolution of the immediate-release microtablets reached 85% at 15 min. Although the dissolution of Formulation 3135-1 reached 98% at 15 min, the release was relatively fast, but still met the requirement of very fast dissolution.

[0127] Figure 6 For the dissolution curves of the respective formulations in Table 6, the abscissa is time, and the ordinate is dissolution. From Figure 6 It can be seen that the dissolution of Formulations 3151 to 3153 was 31% to 32% at 15 min, not less than 80% at 8 h, and reached more than 95% at 12 h. It can be seen that the dissolution trends of Formulations 3151 to 3153 were similar, and the dissolution rate was basically consistent with that of Formulation 3, indicating that under the conditions of the same amount and the same preparation method, using corn starch, low-substituted hydroxypropyl cellulose or cross-linked povidone instead of sodium starch glycolate had little effect on the dissolution of the immediate-release microtablets and the sustained-release microtablets, and met the requirements of the application of fast release of the drug at the early stage and slow release of the drug at the later stage.

[0128] When the amount of sodium starch glycolate in the immediate-release microtablets was 2.02%, the dissolution rate of Formulation 3154 was basically consistent with that of Formulation 3, indicating that the amount of sodium starch glycolate had little effect on the dissolution of Formulation 3154. When the amount of sodium starch glycolate in the immediate-release microtablets was 19.93%, the dissolution rate of Formulation 3155 was basically consistent with that of Formulation 3, indicating that the amount of sodium starch glycolate also had little effect on the dissolution of Formulation 3155. In summary, both Formulations met the requirements of fast release and slow release.

[0129] It should be noted that each complete prescription of the present application is composed of immediate-release microtablets and sustained-release microtablets, for example, prescription 3151 is composed of prescription 3151-1 of immediate-release microtablets and prescription 3-2 of sustained-release microtablets, prescription 3152 is composed of prescription 3152-1 of immediate-release microtablets and prescription 3-2 of sustained-release microtablets, 3153 is composed of prescription 3153-1 of immediate-release microtablets and prescription 3-2 of sustained-release microtablets, 3154 is composed of prescription 3154-1 of immediate-release microtablets and prescription 3-2 of sustained-release microtablets, and 3155 is composed of prescription 3155-1 of immediate-release microtablets and prescription 3-2 of sustained-release microtablets.

[0130] Example 7: Filler Investigation Based on prescription 3 in Example 1, the influence of the type and amount of immediate-release microtablets and sustained-release microtablets on dissolution was investigated, with prescription 3 as a comparative prescription.

[0131] Table 7 Summary of Filler Investigation of Immediate-Release Microtablets and Sustained-Release Microtablets

[0132] The preparation method of each prescription sample in Table 7 is the same as the preparation principle of prescription 3 sample, and will not be repeated here.

[0133] Based on prescription 3, the present application also investigated corn starch, pregelatinized starch, and mannitol as fillers, and investigated the amount of microcrystalline cellulose. With dissolution as the investigation index, the dissolution of prescription 3161 to prescription 3165 of immediate-release microtablets, sustained-release microtablets, and immediate-release microtablets and sustained-release microtablets as a complete prescription was investigated.

[0134] The dissolution of prescription 3161-1 to prescription 3165-1 of immediate-release microtablets reached more than 85% at 15 min, among which, prescription 3164-1 had a relatively slow dissolution rate compared to the remaining prescriptions of the present application, but still met the requirements of very fast dissolution. The dissolution of prescription 3161-2 to prescription 3165-2 of sustained-release microtablets was not less than 10% at 1 h, could reach 60% at 6 h, and was not less than 90% at 12 h, although prescription 3164-1 had a relatively strong sustained-release effect compared to the remaining prescriptions of the present application, but met the requirements of sustained-release dissolution.

[0135] Figure 7For the dissolution curves of each prescription in Table 7, the abscissa is time, and the ordinate is dissolution. As can be seen from the figure, the dissolution of prescriptions 3161 to 3163 is 31%-32% at 15 min, no less than 85% at 8 h, and more than 95% at 12 h. The dissolution rate of prescriptions 3161 to 3163 is basically the same as that of prescription 3, indicating that the three prescriptions meet the requirements of immediate release and sustained release of the present application. In summary, corn starch, pre-gelatinized starch or mannitol is suitable for the immediate release microtablets and sustained release microtablets of the present application.

[0136] By adjusting the amount of lactose and microcrystalline cellulose in the immediate release microtablets and adjusting the amount of microcrystalline cellulose in the sustained release microtablets, the dissolution rates of prescriptions 3164 and 3165 are basically the same as that of prescription 3, meeting the requirements of immediate release and sustained release of the present application.

[0137] It should be noted that each complete prescription of the present application is composed of immediate release microtablets and sustained release microtablets, for example, prescription 3161 is composed of prescription 3161-1 of immediate release microtablets and prescription 3161-2 of sustained release microtablets. The composition of the remaining prescriptions in this example is the same as this case, which will not be repeated here.

[0138] Example 8: Investigation of the effect of capsule shells on immediate release microtablets and sustained release microtablets This example is based on prescription 3 in Example 1, with prescription 3 as a comparative prescription, to investigate the effect of capsule shells on immediate release microtablets and sustained release microtablets.

[0139] Table 8 Summary of the effect of capsule shells on immediate release microtablets and sustained release microtablets

[0140] The prescription 3 preparation in Example 8 is obtained by filling prescription 3-1 immediate release microtablets and prescription 3-2 sustained release microtablets in the capsule shells in Example 1. The preparation method of the immediate release microtablets and the sustained release microtablets of prescription 8 sample is the same as that of prescription 3-1 immediate release microtablets and prescription 3-2 sustained release microtablets, and the amount of raw and auxiliary materials is also the same. The difference lies in that the immediate release microtablets and the sustained release microtablets of prescription 8 are bare tablets, which are not filled into the capsule shells. The preparation method of the sustained release microtablets of prescription 9 is the same as that of prescription 3-2 sustained release microtablets, and the amount of raw and auxiliary materials is also the same. The difference lies in that prescription 9 is obtained by filling only 45 pieces of prescription 3-2 sustained release microtablets into the capsule shells.

[0141] Figure 8For the dissolution curves of each prescription in Table 8, the horizontal axis is time and the vertical axis is dissolution. At 15 min, the dissolution of prescription 3 and prescription 8 can reach 32%, the dissolution at 1 h is 40%, the dissolution at 8 h reaches 85%, and the dissolution at 12 h all reaches more than 95%, which shows that the drug release of the two prescriptions has no obvious difference, indicating that the capsule shell has little effect on the drug release of the immediate-release microtablets and the sustained-release microtablets. The dissolution of prescription 9 at 15 min is 5%, but the dissolution at 8 h can reach 83%, and the dissolution at 12 h can reach 95%, which shows that the capsule shell also has little effect on the drug release of the sustained-release microtablets.

[0142] In summary, the loxoprofen sodium dual-release capsule microtablets of the present application can be taken in the form of whole capsule, or the immediate-release microtablets and the sustained-release microtablets in the capsule can be poured out and taken according to the corresponding number, and the two taking methods have no effect on the drug release. Therefore, the loxoprofen sodium dual-release capsule microtablets of the present application can be taken in any of the above ways.

[0143] Example 9: Pharmacokinetic investigation Test object: Beagle dog; Test sample: commercially available preparation, prescription 3 preparation is the preparation obtained from prescription 3, prescription 7 preparation is the preparation obtained from prescription 7, prescription 8 preparation is the preparation obtained from prescription 8, and prescription 9 preparation is the preparation obtained from prescription 9. Among them, the commercially available preparation is loxoprofen sodium tablets (trade name: Le Song®, specification: 60 mg). The prescription 3 preparation is obtained from the preparation of the prescription in Example 1 of the present application.

[0144] Dosing regimen: as shown in Table 9.

[0145] Table 9 Dosing regimen of Beagle dogs

[0146] Figure 9 In Figure 2, the pharmacokinetic time-concentration curves of the commercially available preparation and the prescription 3 preparation, the horizontal axis is time, and the vertical axis is blood drug concentration.

[0147] Figure 10 In Figure 3, the pharmacokinetic time-concentration curves of the prescription 3 preparation, the prescription 7 preparation, the prescription 8 preparation and the prescription 9 preparation, the horizontal axis is time, and the vertical axis is blood drug concentration.

[0148] By Figure 9It can be seen that both the commercial preparation and the prescription 3 preparation are fast release and absorption, but the commercial preparation is metabolized and eliminated fast, and the blood drug concentration is maintained for a short time. After administration at dinner time, the effective blood drug concentration cannot cover the high incidence period of the disease at night (such as around 3 o'clock in the morning). The prescription 3 preparation can quickly release and absorb to reach the peak, and after the blood drug concentration drops to a certain degree in a short time, the slow-release microtablets slowly release, so that the blood drug concentration rises again and slowly reaches the peak, thereby maintaining the blood drug concentration for a long time. Under the premise of ensuring quick peak effect, the prescription 3 preparation adopts the design of lower specification of the fast-release microtablets than the commercial preparation, which can appropriately reduce the peak concentration and reduce the fluctuation of the blood drug concentration. Moreover, the prescription 3 preparation contains slow-release microtablets, so it can maintain a longer blood drug concentration than the commercial preparation, so that after administration at dinner time, the effective blood drug concentration can cover the high incidence period of the disease at night, significantly reducing the peak-trough ratio of the blood drug concentration and reducing adverse reactions. It can be seen that the absorption speed, peak value and maintenance time of the prescription 3 preparation are balanced, which can quickly take effect and maintain the blood drug concentration for a certain period of time.

[0149] By Figure 10 It can be seen that the prescription 7 preparation takes effect quickly, and after the blood drug concentration quickly reaches the peak, the slow-release microtablets continue to maintain the blood drug concentration for a long time. The blood drug concentration trends of the prescription 3 preparation and the prescription 8 preparation are basically the same, which shows that the capsule shell has no obvious effect on the release and absorption of the drug, indicating that the capsule containing microtablets can be swallowed as a whole or the contents can be directly swallowed. Compared with the prescription 7 preparation, the fast-release peak concentration of the prescription 3 preparation and the prescription 8 preparation is relatively low, but the second peak concentration of the slow-release part of the prescription 3 preparation and the prescription 8 preparation is relatively higher than that of the prescription 7, and the overall blood drug concentration and fluctuation level are comparable. The prescription 9 preparation is a single slow-release capsule containing microtablets, and the blood drug concentration reaches the peak time significantly lags behind the peak time of the prescription 3 preparation, and the initial blood drug concentration is significantly lower than that of the prescription 3, indicating that the effect is slow and cannot meet the needs of urgent analgesia and anti-inflammatory treatment.

[0150] It should also be noted that the term "comprising" or any other variant thereof is intended to cover non-exclusive inclusions, so that a process, method, article or device that includes a series of elements not only includes those elements, but also includes other elements not explicitly listed, or includes elements inherent to such a process, method, article or device. Without more limitations, the element defined by the statement "including at least one" does not exclude the presence of additional identical elements in the process, method, article or device that includes the element.

[0151] Each of the embodiments in the specification is described in a progressive manner, and the same or similar parts between the embodiments can be referred to each other. Each embodiment focuses on the difference from other embodiments.

[0152] Finally, it should be noted that the above only describes the embodiments of the present application, and is only used to explain the technical solutions of the present application, and does not limit the present application. For those skilled in the art, the present application can have various changes and modifications. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the scope of claims of the present application.

Claims

1. A sodium loxoprofen double-release capsule-in-microtablet, characterized by, Comprise: immediate-release microtablets and sustained-release microtablets filled into a capsule shell; wherein, the immediate-release microtablets comprise: an immediate-release microtablet core and a film coating layer wrapped on the surface of the immediate-release microtablet core, the weight of the film coating layer being 5%-20% of the weight of the immediate-release microtablet core; the immediate-release microtablet core comprises, based on the total weight of the immediate-release microtablet core per tablet: 10%-45% of sodium loxoprofen, 25%-75% of a filler, 0.5%-10% of a binder, 2%-20% of a disintegrant, 0.02%-5% of a glidant, and 0.05%-5% of a lubricant; the sustained-release microtablets comprise: a sustained-release microtablet core and a coating layer wrapped on the surface of the sustained-release microtablet core, the weight of the coating layer being 5%-40% of the weight of the sustained-release microtablet core; the sustained-release microtablet core comprises, based on the total weight of the sustained-release microtablet core per tablet: 10%-50% of sodium loxoprofen, 5%-45% of a filler, 10%-70% of a release retardant, 0.05-10% of a binder, 0.02%-5% of a glidant, and 0.05%-5% of a lubricant.

2. The sodium loxoprofen dual-release capsule-in-microtablets according to claim 1, wherein, the content of sodium loxoprofen in each of the immediate-release microtablets and each of the sustained-release microtablets is 0.5 mg-5 mg.

3. The sodium loxoprofen dual-release capsule-in-microtablets according to claim 2, wherein, the content of sodium loxoprofen in each of the immediate-release microtablets is 1-3 mg; and / or, the content of sodium loxoprofen in each of the sustained-release microtablets is 1-3 mg.

4. The sodium loxoprofen dual-release capsule-in-microtablets according to claim 1, wherein, the diameters of the immediate-release microtablets and the sustained-release microtablets are both 1-3 mm; and / or, the total content of sodium loxoprofen in the immediate-release microtablets and the sustained-release microtablets in each capsule is 90 mg.

5. The sodium loxoprofen dual-release capsule-in-microtablets according to claim 1, wherein, the coating layer comprises: an enteric coating layer, or a coating layer wrapped on the surface of the sustained-release microtablet core in sequence by a separation coating layer and an enteric coating layer.

6. The sodium loxoprofen dual-release capsule-in-microtablets according to claim 5, wherein, when the coating layer comprises an enteric coating layer, the enteric coating layer accounts for 15%-40% of the weight percentage of the sustained-release microtablet core; and / or, when the coating layer comprises a separation coating layer and an enteric coating layer, the weight of the separation coating layer accounts for 5%-20% of the weight percentage of the sustained-release microtablet core; the enteric coating layer accounts for 10%-30% of the weight percentage of the total weight of the sustained-release microtablet core and the separation coating layer; and / or, the separation coating layer comprises: a mixture of hypromellose acetate succinate, hydroxypropyl cellulose, and talc, or Opadry®; and / or, The enteric coating layer comprises at least one of methyl acrylic acid-ethyl acrylic acid copolymer, methyl acrylic acid-ethyl acrylic acid copolymer aqueous dispersion, acrylic resin, hydroxypropyl methylcellulose, hydroxypropyl cellulose, talc, triethyl citrate, sodium bicarbonate, colloidal silicon dioxide, Opadry®, and Acryl-EZE®; and / or, The color of the enteric coating layer of the sustained-release microtablet is different from the color of the film coating layer of the immediate-release microtablet.

7. The loxoprofen sodium double-release capsule-in-tablet according to claim 1, wherein The filler in the immediate-release microtablet and the sustained-release microtablet comprises at least one of lactose, microcrystalline cellulose, corn starch, sucrose, pregelatinized starch, and mannitol; and / or, The binder in the immediate-release microtablet and the sustained-release microtablet comprises at least one of povidone, starch paste, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and sodium carboxymethyl cellulose; and / or, The lubricant in the immediate-release microtablet and the sustained-release microtablet comprises at least one of magnesium stearate, talc, sodium stearyl fumarate, calcium stearate, and stearic acid; and / or, The glidant in the immediate-release microtablet and the sustained-release microtablet comprises at least one of talc, colloidal silicon dioxide, and silicon dioxide; and / or, The disintegrant in the immediate-release microtablet comprises at least one of corn starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked povidone, and cross-linked sodium carboxymethyl cellulose; and / or, The release retardant in the sustained-release microtablet comprises at least one of hydroxypropyl methylcellulose, hydroxypropyl cellulose, carbomer, sodium carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, and methyl cellulose; and / or, The film coating layer comprises a mixture of hydroxypropyl methylcellulose, hydroxypropyl cellulose, and talc, or Opadry®.

8. The loxoprofen sodium double-release capsule-in-tablet according to claim 7, wherein When the release retardant in the sustained-release microtablet is hydroxypropyl methylcellulose, the weight ratio of the hydroxypropyl methylcellulose is 10%-55%; and / or, When the filler in the immediate-release microtablet is lactose and microcrystalline cellulose, the weight ratio of the lactose is 25%-50%, and the weight ratio of the microcrystalline cellulose is 7%-32%.

9. The loxoprofen sodium double-release capsule-in-tablet according to any one of claims 1 to 8, wherein The ratio of the total amount of loxoprofen sodium in the immediate-release microtablet to the total amount of loxoprofen sodium in the sustained-release microtablet in each capsule is 1: (0.8-3.5).

10. A process for preparing the sodium loxoprofen double-release capsule minitablets according to any one of claims 1 to 9, characterized by, comprising: The immediate-release microtablet is prepared by the following method: Mixing the prescription amount of loxoprofen sodium with the filler, the binder, and the disintegrant; adding an aqueous ethanol solution, mixing, and preparing a soft material of the immediate-release microtablet; screening the soft material of the immediate-release microtablet, and preparing a wet granule of the immediate-release microtablet; drying and screening the wet granule of the immediate-release microtablet, and preparing a dry granule of the immediate-release microtablet; mixing the dry granule of the immediate-release microtablet with the glidant and the lubricant, and performing a tabletting operation, and preparing a tablet core of the immediate-release microtablet; A film coating liquid is prepared, and the film coating liquid is used to coat the immediate-release microtablet cores to obtain immediate-release microtablets with a film coating layer on the immediate-release microtablet cores; The sustained-release microtablets are prepared by the following method: A prescribed amount of sodium loxoprofen is mixed with a filler and a release retardant, and a binder and an ethanol aqueous solution are added and mixed to prepare a soft material of the sustained-release microtablets; The soft material of the sustained-release microtablets is sieved to prepare wet granules of the sustained-release microtablets; The wet granules of the sustained-release microtablets are dried and sieved to prepare dry granules of the sustained-release microtablets; The dry granules of the sustained-release microtablets are mixed with a glidant and a lubricant, and a tabletting operation is performed to prepare sustained-release microtablet cores; A coating liquid is prepared, and the coating liquid is used to coat the sustained-release microtablet cores to obtain sustained-release microtablets with a coating layer on the sustained-release microtablet cores; The immediate-release microtablets and the sustained-release microtablets are filled into a capsule shell.

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