Multi-release sustained and controlled release composition preparation as well as preparation method and application thereof

Abstract

The invention discloses a multi-release sustained and controlled release composition preparation as well as a preparation method and application thereof. The sustained and controlled release composition preparation comprises sustained and slow release particles and sustained release particles. When the pharmaceutical composition containing dexmethylphenidate hydrochloride is given to a patient in need, the pharmaceutical composition containing dexmethylphenidate hydrochloride is released in the form of three pulses, the action time can be maintained for 14-16 hours, the pharmaceutical composition only needs to be taken once every day, the blood concentration is reduced gently, and the abstinence reaction of the patient can be relieved more easily. The awkward psychology of supplementary medicine taking of children in schools is avoided, and the medicine taking compliance is improved; the in-batch difference is small, the reproducibility is good, and the method is more suitable for commercial production; the abuse prevention effect is achieved, and the abuse of stimulants is avoided.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical preparations, in particular, to a sustained-release composition with three-pulse release for abuse prevention and a preparation method thereof. BACKGROUND

[0002] Methylphenidate is a central nervous system drug that directly stimulates the medullary respiratory center, has a mild effect, and is mainly used for treating attention deficit disorder with mild brain dysfunction, eliminating drowsiness and fatigue caused by barbiturates, respiratory depression caused by excessive anesthesia, various depression, and neurosis, etc. The chemical name of methylphenidate is α-phenyl-2-piperidine acetic acid methyl ester.

[0003] The chemical structure is as follows:

[0004]

[0005] In 2001, Novartis launched Focalin, a methylphenidate hydrochloride tablet, for the treatment of attention deficit hyperactivity disorder (ADHD). In order to increase compliance, in 2005, the company launched Focalin XR, a double-pulse release sustained-release preparation of methylphenidate hydrochloride, which can quickly exert an effect and reach a peak in 1.5-1.9 hours. When the effect of the immediate-release preparation decreases, the sustained-release part starts to release and reaches a peak in 6.5 hours. Compared with the immediate-release preparation, the drug has fewer dosing times, a longer maintenance time, stronger patient compliance, and less addiction, and is suitable for continuously stimulating the medullary respiratory center. However, the drug is usually recommended to be taken in the morning, and if it is taken in the afternoon, it will affect the sleep of the patient. For ADHD patients who have symptoms in the afternoon or evening and need to study and work at night, the treatment time is relatively short, and the concentration can only be improved by adding immediate-release methylphenidate hydrochloride to improve concentration.

[0006] The existing double-pulse release methylphenidate hydrochloride preparation has the following problems: after the second release, the blood drug concentration continues to decrease after reaching the peak, and the patient needs to take the drug again to reach the effective value when working or studying at night. The two dosing times have the following problems: ① poor patient compliance; ② the blood drug concentration peak is too high when taking the drug again at night, which affects the rest after working or studying at night.

[0007] Chinese patent CN111557929A discloses a methylphenidate hydrochloride multiple release preparation, which places the drug-containing part on the same pellet by layer-by-layer coating and separates them with a sustained-release layer to achieve gradient release of the drug. However, the preparation does not have obvious three-pulse release results.

[0008] US20210077417A1 discloses an oral solid preparation of dexmethylphenidate hydrochloride, which comprises a plurality of coated beads, has a fast-acting therapeutic effect in daily activities, and a duration of action of at least 14 hours. The three-pulse drug release platform therein is ECCRIR beads (30%) + DRCRIR beads (55%) + IR beads (15%), but mixing the three beads to obtain an oral preparation has the problems of poor uniformity, unobvious three-pulse drug release, and difficulty in industrialization. In addition, dexmethylphenidate abuse is also prone to occur.

[0009] It can be seen that although some multiple release preparations of dexmethylphenidate have been disclosed in the prior art, they generally have the problems of mutual influence between each multiple release, unstable preparation quality, and easy drug abuse, and therefore, a new multiple release preparation of dexmethylphenidate needs to be developed to meet people's needs. SUMMARY

[0010] The following is a summary of the subject matter described in detail herein. This summary is not intended to limit the scope of the claims.

[0011] Therefore, the technical problem to be solved by the present application is to provide a sustained-release composition preparation, which fills the current technical gap, has a higher drug concentration during the learning and working time of patients, reduces the mutual influence between each multiple release, has obvious three-pulse drug release effect, and effectively prevents the abuse of methylphenidate, especially dexmethylphenidate hydrochloride, has better uniformity when two kinds of microparticles are loaded into the same solid dosage form, is easy to industrialize, makes the compliance of patients taking the medicine stronger, and reduces the addiction.

[0012] The first aspect of the present application provides a sustained-release composition preparation, comprising sustained-release microparticles and slow-release microparticles.

[0013] In an exemplary embodiment, the weight ratio of the sustained-release microparticles to the slow-release microparticles is 0.5:1 to 1.5:1.

[0014] In an exemplary embodiment, the weight ratio of the sustained-release microparticles to the slow-release microparticles is 0.9:1 to 1.2:1.

[0015] In an exemplary embodiment, the weight ratio of the sustained-release microparticles to the slow-release microparticles is 0.91:1, 0.76:1, 0.82:1, 0.77:1, 1.2:1, 0.93:1, or 1.11:1.

[0016] In an exemplary embodiment, the diameter of the slow-release microparticles and the sustained-release microparticles is 0.3-2.8mm, preferably 1.0-2.5mm.

[0017] In an exemplary embodiment, the sustained-release microparticle comprises a blank core I and a sustained-release layer I and an immediate-release layer arranged outside the sustained-release layer I in sequence.

[0018] In an exemplary embodiment, the sustained-release microparticle comprises a blank core II and a sustained-release layer II arranged outside the blank core II.

[0019] In an exemplary embodiment, the weight ratio of the sustained-release coating layer I to the sustained-release coating layer II is 0.5:1-1:1.

[0020] In an exemplary embodiment, the weight ratio of the sustained-release coating layer I to the sustained-release coating layer II is 0.67:1, 0.57:1, 0.64:1, 0.71:1, 0.77:1 or 0.54:1.

[0021] In an exemplary embodiment, the active ingredient comprises atomoxetine, a stereoisomer of atomoxetine or a pharmaceutically acceptable salt thereof.

[0022] In an exemplary embodiment, the active ingredient is dexatomoxetine hydrochloride.

[0023] In an exemplary embodiment, the total content of the active ingredient in the sustained-release and controlled-release composition preparation is 5-80 mg.

[0024] In an exemplary embodiment, the blank core I and the blank core II each comprise a core body.

[0025] In an exemplary embodiment, the core body comprises a filler and an abuse-preventing adjuvant, and optionally, a binder and / or a lubricant.

[0026] In an exemplary embodiment, the filler is selected from one or several combinations of compressible starch, powdered sugar, dextrin, calcium sulfate, lactose, mannitol, sorbitol, dextrin and microcrystalline cellulose. Herein, the “compressible starch” is also known as pregelatinized starch, for example, corn starch.

[0027] In an exemplary embodiment, the content of the filler is 30%-80% based on the total weight of the core body.

[0028] In an exemplary embodiment, the content of the filler is 35%-60% based on the total weight of the core body.

[0029] In an exemplary embodiment, the content of the filler is 30%, 33%, 37%, 40%, 41%, 42%, 45%, 47%, 50%, 55%, 60%, 65%, 70%, 75%, 80% based on the total weight of the core body.

[0030] In an exemplary embodiment, the filler content is 37.0%, 41.0%, 41.1%, 47.0%, 50.5%, 60.0% by weight of the total weight of the core.

[0031] In an exemplary embodiment, the abuse deterrent excipient is selected from one or more of gum arabic, xanthan gum, pectin, carrageenan, gelatin, guar gum, gum tragacanth, agar, alginic acid, sodium alginate, propylene glycol alginate, polyoxyethylene, carbomer, beta-cyclodextrin, hydroxypropyl starch, hydroxyethyl starch, chitosan, polyvinylpyrrolidone.

[0032] In an exemplary embodiment, the abuse deterrent excipient content is 20%-70% by weight of the total weight of the core.

[0033] In an exemplary embodiment, the abuse deterrent excipient content is 25%-55% by weight of the total weight of the core.

[0034] In an exemplary embodiment, the abuse deterrent excipient content is 25%, 27%, 30%, 33%, 34%, 35%, 37%, 38%, 39%, 40%, 43%, 45%, 47%, 50%, 53%, 55%, 56%, 58%, 60%, 62%, 65%, 67%, 68%, 70% by weight of the total weight of the core.

[0035] In an exemplary embodiment, the abuse deterrent excipient content is 27.1%, 34.1%, 38.9%, 45.7%, 50.2%, 55.5% by weight of the total weight of the core.

[0036] In an exemplary embodiment, the lubricant is selected from one or more of sodium stearyl fumarate, talc, stearic acid, magnesium stearate.

[0037] In an exemplary embodiment, the binder is selected from one or more of starch paste, polyethylene glycol-4000, polyethylene glycol-6000, polyvinyl alcohol, methyl cellulose, hypromellose, hydroxypropyl cellulose, ethyl cellulose, povidone, and polyvinyl pyrrolidone.

[0038] In an exemplary embodiment, the binder is selected from one or more of starch paste, methyl cellulose, hypromellose, hydroxypropyl cellulose, ethyl cellulose, povidone, or polyvinyl pyrrolidone.

[0039] In an exemplary embodiment, the core composition of the blank core I and the blank core II are the same or different.

[0040] In an exemplary embodiment, the core bodies of the blank core I and the blank core II are manufactured simultaneously using the same pharmaceutically acceptable excipient.

[0041] In an exemplary embodiment, the core bodies of the blank core I and the blank core II respectively comprise lactose, acacia and sodium alginate.

[0042] In an exemplary embodiment, the core bodies of the blank core I and the blank core II respectively comprise polyoxyethylene, lactose, mannitol, alginic acid and magnesium stearate.

[0043] In an exemplary embodiment, the core bodies of the blank core I and the blank core II respectively comprise dextrin, xanthan gum, hydroxypropyl cellulose, sodium alginate and β-cyclodextrin.

[0044] In an exemplary embodiment, the core bodies of the blank core I and the blank core II respectively comprise microcrystalline cellulose, pectin and agar.

[0045] In an exemplary embodiment, the core bodies of the blank core I and the blank core II respectively comprise corn starch, acacia, polyoxyethylene and sodium stearyl fumarate.

[0046] In an exemplary embodiment, the core bodies of the blank core I and the blank core II respectively comprise sorbitol, tragacanth gum, chitosan and stearic acid.

[0047] In an exemplary embodiment, the core bodies of the blank core I and the blank core II respectively comprise microcrystalline cellulose, guar gum co-processed, carbomer and magnesium stearate.

[0048] In an exemplary embodiment, the surface layer of the core bodies of the blank core I and the blank core II is further coated with a blank isolation layer, respectively.

[0049] In an exemplary embodiment, the blank isolation layer contains one or more pharmaceutically acceptable excipients selected from Opadry White series, Opadry Clear series, Opadry II series, hydroxypropyl cellulose, hypromellose, ethyl cellulose, polyethylene glycol, titanium dioxide, talc.

[0050] In an exemplary embodiment, the blank isolation layer contains one or more pharmaceutically acceptable excipients selected from hydroxypropyl cellulose, hypromellose, Opadry Clear Opadry Clear YS-1-7006.

[0051] In an exemplary embodiment, the sustained release layer I comprises a drug-containing layer I and a sustained release coating layer I; the sustained release layer II comprises a drug-containing layer II and a sustained release coating layer II.

[0052] In an exemplary embodiment, the immediate release layer, the drug-containing layer I, the drug-containing layer II each comprises an active ingredient and a binder.

[0053] In an exemplary embodiment, the immediate release layer comprises a first dosage of an active ingredient, a binder, and optionally a disintegrant.

[0054] In an exemplary embodiment, the drug-containing layer I comprises a second dosage of an active ingredient and a binder.

[0055] In an exemplary embodiment, the drug-containing layer II comprises a third dosage of an active ingredient and a binder.

[0056] In an exemplary embodiment, the content of the binder in the immediate release layer is 1.00%-30% based on the total weight of the immediate release layer.

[0057] In an exemplary embodiment, the content of the binder in the immediate release layer is 7.5%-30% based on the total weight of the immediate release layer.

[0058] In an exemplary embodiment, the content of the binder in the immediate release layer is 10%-30% based on the total weight of the immediate release layer.

[0059] In an exemplary embodiment, the content of the binder in the immediate release layer is 7.94%, 13.11%, 17.29%, 20.00%, 25.81%, 27.47% or 28.57% based on the total weight of the immediate release layer.

[0060] In an exemplary embodiment, the content of the binder in the drug-containing layer I is 1%-30% based on the total weight of the drug-containing layer I.

[0061] In an exemplary embodiment, the content of the binder in the drug-containing layer I is 10%-30% based on the total weight of the drug-containing layer I.

[0062] In an exemplary embodiment, the content of the binder in the drug-containing layer I is 12.85%, 16.67%, 18.92%, 25%, 26.47%, 27.18% or 28.57% based on the total weight of the drug-containing layer I.

[0063] In an exemplary embodiment, the content of the binder in the drug-containing layer II is 1%-65% based on the total weight of the drug-containing layer II.

[0064] In an exemplary embodiment, the content of the binder in the drug-containing layer II is 25%-45% based on the total weight of the drug-containing layer II.

[0065] In an exemplary embodiment, the content of the adhesive in the drug-containing layer II is 7.74%, 12.5%, 25.00%, 28.57%, 29.00%, 29.41% or 29.47% based on the total weight of the drug-containing layer II.

[0066] In an exemplary embodiment, the weight of the active ingredient in the immediate-release layer accounts for 30%-40% of the total weight of the active ingredient, the weight of the active ingredient in the drug-containing layer I accounts for 35%-50% of the total weight of the active ingredient, and the weight of the active ingredient in the drug-containing layer II accounts for 10%-35% of the total weight of the active ingredient.

[0067] In an exemplary embodiment, the weight of the active ingredient in the immediate-release layer accounts for 35% of the total weight of the active ingredient, the weight of the active ingredient in the drug-containing layer I accounts for 35% of the total weight of the active ingredient, and the weight of the active ingredient in the drug-containing layer II accounts for 30% of the total weight of the active ingredient.

[0068] In an exemplary embodiment, the weight of the active ingredient in the immediate-release layer accounts for 35% of the total weight of the active ingredient, the weight of the active ingredient in the drug-containing layer I accounts for 40% of the total weight of the active ingredient, and the weight of the active ingredient in the drug-containing layer II accounts for 25% of the total weight of the active ingredient.

[0069] In an exemplary embodiment, the weight of the active ingredient in the immediate-release layer accounts for 32% of the total weight of the active ingredient, the weight of the active ingredient in the drug-containing layer I accounts for 50% of the total weight of the active ingredient, and the weight of the active ingredient in the drug-containing layer II accounts for 18% of the total weight of the active ingredient.

[0070] In an exemplary embodiment, the weight of the active ingredient in the immediate-release layer accounts for 30% of the total weight of the active ingredient, the weight of the active ingredient in the drug-containing layer I accounts for 50% of the total weight of the active ingredient, and the weight of the active ingredient in the drug-containing layer II accounts for 20% of the total weight of the active ingredient.

[0071] In an exemplary embodiment, the weight of the active ingredient in the immediate-release layer accounts for 40% of the total weight of the active ingredient, the weight of the active ingredient in the drug-containing layer I accounts for 40% of the total weight of the active ingredient, and the weight of the active ingredient in the drug-containing layer II accounts for 20% of the total weight of the active ingredient.

[0072] In an exemplary embodiment, the adhesive is selected from one or a combination of starch paste, polyethylene glycol-4000, polyethylene glycol-6000, polyvinyl alcohol, methyl cellulose, hypromellose, hydroxypropyl cellulose, ethyl cellulose, povidone and polyvinylpyrrolidone.

[0073] In an exemplary embodiment, the binder in the immediate release layer, the binder in the sustained release layer I and the binder in the sustained release layer II are the same or different.

[0074] In an exemplary embodiment, the binder in the immediate release layer, the binder in the sustained release layer I and the binder in the sustained release layer II are the same or different.

[0075] In an exemplary embodiment, the binder in the immediate release layer, the binder in the sustained release layer I and the binder in the sustained release layer II are the same or different.

[0076] In an exemplary embodiment, the binder in the immediate release layer, the binder in the sustained release layer I and the binder in the sustained release layer II are the same or different.

[0077] In an exemplary embodiment, the binder in the immediate release layer, the binder in the sustained release layer I and the binder in the sustained release layer II are the same or different.

[0078] In an exemplary embodiment, the binder in the immediate release layer is low-substituted hydroxypropyl cellulose, the binder in the sustained release layer I is polyvinylpyrrolidone, and the binder in the sustained release layer II is a mixture of methyl cellulose and polyvinylpyrrolidone.

[0079] In an exemplary embodiment, the binder in the immediate release layer is low-substituted hydroxypropyl cellulose, the binder in the sustained release layer I is polyvinylpyrrolidone, and the binder in the sustained release layer II is a mixture of methyl cellulose and polyvinylpyrrolidone.

[0080] In an exemplary embodiment, the binder in the immediate release layer is low-substituted hydroxypropyl cellulose, the binder in the sustained release layer I is polyvinylpyrrolidone, and the binder in the sustained release layer II is a mixture of methyl cellulose and polyvinylpyrrolidone.

[0081] In an exemplary embodiment, the content of the disintegrant in the immediate release layer is 5%-40% based on the total weight of the immediate release layer.

[0082] In an exemplary embodiment, the content of the disintegrant in the immediate release layer is 5%-30% based on the total weight of the immediate release layer.

[0083] In an exemplary embodiment, the content of the disintegrant in the immediate release layer is 5%, 7%, 8%, 10%, 13%, 15%, 17%, 18%, 20%, 22%, 23%, 25%, 27%, 28%, 30%, 33%, 35%, 38%, 40% based on the total weight of the immediate release layer.

[0084] In an exemplary embodiment, the content of the disintegrant in the immediate release layer is 7.4%, 13.1%, 17.6%, 20%, 25.8%, 27.5% or 28.6% based on the total weight of the immediate release layer.

[0085] In an exemplary embodiment, the disintegrant can be selected from one or a combination of dry starch, crosscarmellose sodium, carmellose sodium, carmellose starch, low-substituted hydroxypropyl cellulose.

[0086] In an exemplary embodiment, the sustained release coating layer I and the sustained release coating layer II each comprise an enteric coating material and a plasticizer, and optionally one or more of an anti-tacking agent and an opacifying agent.

[0087] In an exemplary embodiment, the content of the enteric coating material is 20%-98% based on the weight of the sustained release coating layer I or the sustained release coating layer II; optionally, 50%-98%.

[0088] In an exemplary embodiment, the content of the enteric coating material is 50%, 55%, 60%, 61%, 62%, 65%, 67%, 70%, 72%, 75%, 78%, 80%, 82%, 83%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 98% based on the weight of the sustained release coating layer I or the sustained release coating layer II; or

[0089] The content of the enteric coating material is 61.6%, 70%, 82.6%, 86.8%, 92.65%, 92.8% or 94.0%.

[0090] In an exemplary embodiment, the enteric coating material is selected from one or a combination of methacrylic acid copolymers (such as EUDRAGIT L100, S 100, L100-55, L 30D-55, FS 30D, NE 30D, etc.), aminomethacrylic acid copolymers (such as EUDRAGIT E 100, RL 100, RS 100, RL 30D, RS 30D, E PO, etc.), hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate.

[0091] In an exemplary embodiment, the content of the plasticizer is 2%-80% based on the weight of the sustained release coating layer I or the sustained release coating layer II.

[0092] In an exemplary embodiment, the content of the plasticizer is 2%-60% based on the weight of the sustained release coating layer I or the sustained release coating layer II.

[0093] In an exemplary embodiment, the content of the plasticizer is 2-40% by weight of the sustained release coating layer I or the sustained release coating layer II.

[0094] In an exemplary embodiment, the content of the plasticizer is 5-20% by weight of the sustained release coating layer I or the sustained release coating layer II.

[0095] In an exemplary embodiment, the content of the plasticizer is 5%, 6%, 7%, 8%, 10%, 11%, 15%, 16%, 17%, 18%, 19%, 20% by weight of the sustained release coating layer I or the sustained release coating layer II; or

[0096] The content of the plasticizer is 5.5%, 5.7%, 6.0%, 7.0%, 7.4%, 7.8%, 10.2%, 16.1% or 16.4%.

[0097] In an exemplary embodiment, the plasticizer is selected from one or more of propylene glycol, glycerin, polyethylene glycol, castor oil, diethyl phthalate, triethyl citrate, acetyl tri-butyl citrate, acetyl tri-ethyl citrate, polyvinyl alcohol.

[0098] In an exemplary embodiment, the anti-adhesion agent is selected from one or more of talc, stearic acid micronized silica gel.

[0099] In an exemplary embodiment, the light shielding agent is selected from one or more of titanium dioxide, zinc oxide, calcium carbonate, talc.

[0100] In an exemplary embodiment, the enteric coating material in the sustained release coating layer I and the enteric coating material in the sustained release coating layer II are the same or different.

[0101] In an exemplary embodiment, the enteric coating material in the sustained release coating layer I is Eudragit S100, and the enteric coating material in the sustained release coating layer II is a combination of Eudragit FS 30D and Eudragit RL 100.

[0102] In an exemplary embodiment, the enteric coating material in the sustained release coating layer I is Eudragit RL PO, and the enteric coating material in the sustained release coating layer II is a combination of Eudragit RL PO, Eudragit R and Eudragit L 100.

[0103] In an exemplary embodiment, the enteric coating material in the sustained release coating layer I is cellulose acetate phthalate, and the enteric coating material in the sustained release coating layer II is Eudragit L100-55.

[0104] In an exemplary embodiment, the enteric coating material in the sustained release coating layer I is Eudragit L 30D-55, and the enteric coating material in the sustained release coating layer II is a combination of Eudragit L 30D-55 and Eudragit RS 30D.

[0105] In an exemplary embodiment, the enteric coating material in the sustained release coating layer I is a combination of Eudragit EPO and Eudragit S 100, and the enteric coating material in the sustained release coating layer II is a combination of hypromellose phthalate and Eudragit S 100.

[0106] In an exemplary embodiment, the enteric coating material in the sustained release coating layer I is a combination of Eudragit L 100-55 and Eudragit NE 30D, and the enteric coating material in the sustained release coating layer II is a combination of Eudragit RL 100 and Eudragit FS 30D.

[0107] In an exemplary embodiment, the enteric coating material in the sustained release coating layer I is a combination of hypromellose phthalate and Eudragit RL PO, and the enteric coating material in the sustained release coating layer II is a combination of Eudragit RL 100 and Eudragit RL 30D.

[0108] In an exemplary embodiment, the plasticizer in the sustained release coating layer I and the plasticizer in the sustained release coating layer II are the same or different.

[0109] In an exemplary embodiment, the plasticizer in the sustained release coating layer I and the plasticizer in the sustained release coating layer II are both polyvinyl alcohol.

[0110] In an exemplary embodiment, the plasticizer in the sustained release coating layer I and the plasticizer in the sustained release coating layer II are both triethyl citrate.

[0111] In an exemplary embodiment, the plasticizer in the sustained release coating layer I and the plasticizer in the sustained release coating layer II are both acetyl tri-butyl citrate.

[0112] In an exemplary embodiment, the plasticizer in the sustained release coating layer I is polyethylene glycol, and the plasticizer in the sustained release coating layer II is triethyl citrate.

[0113] In an exemplary embodiment, the plasticizer in the sustained release coating layer I is acetyl tri-butyl citrate, and the plasticizer in the sustained release coating layer II is diethyl phthalate.

[0114] In an exemplary embodiment, the plasticizer in the sustained release coating layer I is diethyl phthalate, and the plasticizer in the sustained release coating layer II is triethyl citrate.

[0115] In an exemplary embodiment, the anti-tacking agent is talc.

[0116] In an exemplary embodiment, the modified release composition is formulated for oral administration directly as a multiparticulate or in a capsule.

[0117] In an exemplary embodiment, the modified release composition is a modified release capsule containing dextroamphetamine hydrochloride, the capsule containing 2 minitablets.

[0118] In an exemplary embodiment, the modified release composition is a modified release capsule containing dextroamphetamine hydrochloride, the capsule containing 2 minitablets.

[0119] In an exemplary embodiment, the blank separating layer of the modified release capsule containing the minitablets is Opadry®-Clear YS-1-7006.

[0120] In an exemplary embodiment, the blank separating layer of the modified release capsule containing the minitablets is Opadry®-Clear YS-1-7006.

[0121] In an exemplary embodiment, the modified release composition is formulated for oral administration directly as a multiparticulate or in a capsule.

[0122] (a) immediate release minitablets comprising:

[0123] (i) a core of the blank core I comprising a filler and an abuse deterrent adjunct;

[0124] (ii) a blank separating layer of the blank core I;

[0125] (iii) a drug-containing layer I comprising an active ingredient and a binder;

[0126] (iv) a sustained release coating layer I comprising an enteric coating material, a plasticizer, and an anti-tacking agent; and

[0127] (v) an immediate release layer comprising an active ingredient and a binder;

[0128] and

[0129] (b) sustained release minitablets comprising:

[0130] (i) a core of the blank core II comprising a filler and an abuse deterrent adjunct;

[0131] (ii) a blank separating layer of the blank core II;

[0132] (iii) a drug-containing layer II comprising an active ingredient and a binder;

[0133] (iv) a sustained release coating layer II comprising an enteric coating material, a plasticizer, and an anti-tacking agent.

[0134] In an exemplary embodiment, the filler in the blank core I and the blank core II is one or both of lactose and mannitol; the abuse deterrent excipient is one or both of polyoxyethylene and alginic acid;

[0135] The blank separating layer comprises Opadry Clear YS-1-7006;

[0136] The binder of the drug-containing layer I is one or both of povidone and hydroxypropyl cellulose;

[0137] In the sustained-release coating layer I and the sustained-release coating layer II, the enteric coating material is selected from one or more of methacrylic acid copolymer, aminomethacrylic acid copolymer, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate; the plasticizer is triethyl citrate; the anti-adhesive is talc;

[0138] The binder of the immediate-release layer and the drug-containing layer II is hydroxypropyl cellulose.

[0139] In an exemplary embodiment, the salted hydroxypropyl methylcellulose sustained-release composition preparation comprises:

[0140] (a) sustained-release microparticles, comprising:

[0141] (i) the core of the blank core I, comprising a filler, an abuse deterrent excipient, and a binder;

[0142] (ii) the blank separating layer of the blank core I;

[0143] (iii) the drug-containing layer I, comprising an active ingredient and a binder;

[0144] (iv) the sustained-release coating layer I, comprising an enteric coating material, a plasticizer, an anti-adhesive, and an opacifier; and

[0145] (v) the immediate-release layer, comprising an active ingredient and a binder;

[0146] and

[0147] (b) sustained-release microparticles, comprising:

[0148] (i) the core of the blank core II, comprising a filler, an abuse deterrent excipient, and a binder;

[0149] (ii) the blank separating layer of the blank core II;

[0150] (iii) the drug-containing layer II, comprising an active ingredient and a binder;

[0151] (iv) the sustained-release coating layer II, comprising an enteric coating material, a plasticizer, and an anti-adhesive.

[0152] In an exemplary embodiment, the filler in the blank core I and the blank core II is dextrin; the abuse-preventing adjuvant is one or more of xanthan gum, sodium alginate, and β-cyclodextrin;

[0153] The blank separating layer comprises one or more of hydroxypropyl cellulose, hypromellose, polyethylene glycol, and titanium dioxide;

[0154] The adhesive in the drug-containing layer I is hydroxypropyl cellulose;

[0155] The enteric coating material in the sustained-release coating layer I is selected from one or more of methacrylic acid copolymer, aminomethacrylic acid copolymer, hypromellose phthalate, and hypromellose acetate succinate; the plasticizer is polyethylene glycol, the opacifier is titanium dioxide, and the anti-adhesive is talc;

[0156] The adhesive in the immediate-release layer is hypromellose;

[0157] The adhesive in the drug-containing layer II is hypromellose;

[0158] The enteric coating material of the sustained-release coating layer II is selected from one or more of methacrylic acid copolymer, aminomethacrylic acid copolymer, hypromellose phthalate, and hypromellose acetate succinate; the plasticizer is triethyl citrate, and the anti-adhesive is talc.

[0159] A second aspect of the present application provides a preparation method of the above-mentioned sustained-release composition, which is a sustained-release capsule containing dextroamphetamine hydrochloride, and the capsule contains two micro-tablets, and the method comprises the following steps:

[0160] (1) Preparation of blank core I and blank core II

[0161] Mix the core materials of the blank core I and the blank core II uniformly and perform tabletting to obtain a tablet core;

[0162] Disperse the separating layer materials uniformly in water, and then use a coating machine to perform separating coating on the tablet core of the blank core I and the blank core II to obtain the blank core I and the blank core II;

[0163] (2) Preparation of sustained-release micro-tablet

[0164] Disperse the drug-containing layer I, the sustained-release coating layer I, and the immediate-release layer materials uniformly in water or an aqueous ethanol solution to obtain a drug-containing layer I liquid, a sustained-release coating layer I liquid, and an immediate-release layer liquid;

[0165] The blank core I is coated and dried using a coating machine in sequence with the drug-containing layer I liquid, the sustained-release coating layer I liquid and the immediate-release layer liquid; and a sustained-release microtablet is obtained.

[0166] (3) Preparation of sustained-release microtablet

[0167] The raw materials of the drug-containing layer II and the sustained-release coating layer II are uniformly dispersed in water or an ethanol aqueous solution to obtain a drug-containing layer II liquid and a sustained-release coating layer II liquid;

[0168] The blank core II is coated and dried using a coating machine in sequence with the drug-containing layer II liquid and the sustained-release coating layer II liquid; and a sustained-release microtablet is obtained.

[0169] (4) Capsule filling

[0170] The sustained-release microtablet and the sustained-release and immediate-release microtablet are filled into capsules, and the sustained-release and immediate-release capsule is obtained.

[0171] A third aspect of the present application provides a preparation method of a sustained-release and controlled-release composition preparation, which is a sustained-release and controlled-release capsule containing dexamphetamine hydrochloride, and the capsule contains two kinds of microtablets, and the method comprises the following steps:

[0172] (1) Preparation of blank core I and blank core II

[0173] The core body raw materials of the blank core I and the blank core II are uniformly mixed and then extruded to prepare a pill-shaped core body;

[0174] The blank isolation layer raw materials are uniformly dispersed in water, and the pill-shaped core body of the blank core I and the blank core II is respectively coated with an isolation layer using a fluidized bed to obtain the blank core I and the blank core II;

[0175] (2) Preparation of sustained-release and immediate-release microtablet

[0176] The raw materials of the drug-containing layer I, the sustained-release coating layer I and the immediate-release layer are uniformly dispersed in water or an ethanol aqueous solution to obtain a drug-containing layer I liquid, a sustained-release coating layer I liquid and an immediate-release layer liquid;

[0177] The blank core I is coated and dried using a fluidized bed in sequence with the drug-containing layer I liquid, the sustained-release coating layer I liquid and the immediate-release layer liquid; and a sustained-release and immediate-release microtablet is obtained.

[0178] (3) Preparation of sustained-release microtablet

[0179] The raw materials of the drug-containing layer II and the sustained-release coating layer II are uniformly dispersed in water or an ethanol aqueous solution to obtain a drug-containing layer II liquid and a sustained-release coating layer II liquid;

[0180] The blank core II is coated and dried using a fluidized bed in sequence with the drug-containing layer II liquid and the sustained-release coating layer II liquid; and a sustained-release microtablet is obtained.

[0181] (4) Capsule filling

[0182] Capsule filling of the sustained-release pellets and the sustained and delayed-release pellets is performed, and thus the sustained and delayed-release pellets are obtained.

[0183] The fourth aspect of the present application provides a use of the above-mentioned sustained and controlled-release composition in the preparation of a drug for treating a mental disease, wherein the mental disease is attention deficit hyperactivity disorder.

[0184] Methylphenidate, particularly dexmethylphenidate hydrochloride, is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). Symptoms of ADHD include hyperactivity, impulsivity, or inattention, which are present before 7 years of age and cause clinically significant impairment. The efficacy of dexmethylphenidate hydrochloride for the treatment of hyperactivity has been established in two controlled clinical studies of patients 6 to 17 years of age who met DSM-IV criteria for hyperactivity. Symptoms must have been present for at least 6 months and were present in two or more settings, e.g., at home, school, or work; and in at least one setting, e.g., in the school or at work or at home. For the Inattentive Type, at least 6 of the following symptoms must have persisted for more than 6 months: failure to give close attention to details / gross mistakes in schoolwork; lack of sustained attention; does not listen to instructions; failure to finish tasks; disorganization; avoids tasks requiring sustained mental effort; loses things; easily distracted; forgetful. For the Hyperactive-Impulsive Type, at least 6 of the following symptoms must have persisted for more than 6 months: fidgeting / squirms in seat; leaves seat in situations when remaining seated is expected; runs about or climbs in inappropriate situations; difficulty playing or engaging in leisure activities quietly; excessively active; talks excessively; blurt answers; difficulty in waiting for one's turn; interrupts or intrudes on others. The Combined Type indicates both inattentiveness and overactivity, impulsivity.

[0185] ADHD is generally considered to require long-term pharmacological treatment. When the drug is temporarily or permanently stopped, the condition can continue to improve. If abnormal symptoms worsen or other adverse events occur, the dose should be reduced, or the drug should be stopped if necessary. If improvement is not observed after 1 month of appropriate dose adjustment, the drug should be stopped.

[0186] Compared with the prior art, the present application has the following technical effects:

[0187] The first object of the present application is to design a dexmethylphenidate hydrochloride long-acting sustained-release preparation with three-pulse release, which can achieve three releases at a time, the third release before learning or working at night, so that the patient does not need to take the drug again; at the same time, the blood concentration peak reached by the third release is lower than that reached by direct re-dosing, and the blood concentration has decreased to a lower value during the rest time at night, which does not affect the rest of the patient at night, so as to ensure the normal learning of the patient in the morning and evening and the normal rest of the patient during the period.

[0188] The second object of the present application is to avoid the abuse of psychotropic drugs by nasal inhalation, chewing, injection and the like by preparing an abuserepellent triple-pulse sustained-release pharmaceutical preparation, and to avoid the destruction of the sustained-release coating material by crushing or grinding, thereby filling the gap in the research on the abuse-repellent of the injection extraction and nasal inhalation after the marketed product is not crushed.

[0189] The composition preparation described in the present application takes effect after 30 minutes, the active ingredient in the sustained-release layer I is released in 2-5 hours, and the active ingredient in the sustained-release layer II is released in 5-9 hours. As illustrated by the data in each example, the composition preparation of the present application can maintain a relatively high drug concentration during the learning and working time, has obvious triple-pulse drug release effect, ensures the normal learning of the patient in the morning, noon and evening and the normal rest during the period; mixing two kinds of microtablets or microparticles in one solid preparation improves the process robustness, mixing uniformity, and less mutual influence, so that it is easy to be industrialized; the abuse-repellent process is increased to prevent the abuser from destroying the sustained-release coating material by crushing or grinding, and then using nasal inhalation, chewing, injection and the like to abuse psychotropic drugs.

[0190] Other features and advantages of the present application will be set forth in the following description, and in part will become apparent to those skilled in the art from the description, or can be learned by practice of the present application. Other advantages of the present application can be realized and attained by means of the instrumentalities and combinations particularly pointed out in the description and appended claims. BRIEF DESCRIPTION OF DRAWINGS

[0191] The accompanying drawings are included to provide an understanding of the technical solutions of the present application, and constitute a part of the specification, and are used together with the embodiments of the present application to explain the technical solutions of the present application, and do not constitute a limitation on the technical solutions of the present application.

[0192] Figure 1 Dissolution curve of the in-batch sample of Comparative Example 1;

[0193] Figure 2 Dissolution curve of the in-batch sample of Example 1;

[0194] Figure 3 Average dissolution curve of the samples of Example 1 to Example 7, Comparative Example 1 and Comparative Example 2;

[0195] Figure 4 In-vivo drug concentration-time results of the samples of Example 1, Example 5, Comparative Example 1 and Comparative Example 2. DETAILED DESCRIPTION

[0196] The present application provides the following definitions in order to more precisely describe the present application. Otherwise all terms will be according to their ordinary meaning as interpreted by one of ordinary skill in the art (i.e. pharmaceutical drug formulation).

[0197] The term "effective drug concentration" as used herein is defined as an active drug (e.g., dexmethylphenidate) or salt thereof that is sufficient to elicit a reasonably observable biological response when administered to a patient. It will be appreciated that the precise therapeutic dose will depend on the age and condition of the patient and the nature of the condition to be treated, as well as final considerations to be made by the attending physician.

[0198] The term "therapeutic effect" or "treatment" as used herein when referring to a condition, and as understood in the art, is defined as referring to a method for obtaining beneficial or desired results, including clinical results. "Treatment" can also refer to prolonging the survival of a subject when compared to the expected survival rate of a subject who does not receive treatment.

[0199] The term "drug" as used herein refers to oral dosage forms, including but not limited to all modified release dosage forms, osmotic controlled release systems, erosion controlled release systems, dissolution controlled release systems, diffusion controlled release systems, matrix tablets, enteric coated tablets, monolayer and bilayer coated tablets (including extended release and enhanced absorption tablets as described herein), capsules, minitablets, caplets, coated beads, granules, spheroids, pellets, microparticles, suspension compositions.

[0200] The term "microparticle" as used herein refers to a drug formulation in discrete microparticle form, and is interchangeable with the terms "microsphere," "spheroid particle," "microcapsule," "granule," "multiparticulate," "pellet," "spheroid," "bead," and "pellet."

[0201] The term "tablet" as used herein refers to a single dosage form, i.e., a single entity that is administered to a subject that contains an active agent. The term "tablet" also includes tablets that can be a combination of one or more "microtablets."

[0202] The term "capsule" as used herein refers to a single dosage form, i.e., a single entity that is administered to a subject that contains an active agent. The term "capsule" also includes capsules that can be a combination of one or more "microcapsules."

[0203] The terms "sustained release," "long duration," as used herein, are defined to extend the time of drug release for therapeutic or convenience purposes not provided by conventional immediate release dosage forms. The rate of active drug release is controlled by the characteristics of the dosage form and / or in combination with physiological or environmental conditions, rather than solely by physiological or environmental conditions. The sustained release dosage forms of certain embodiments can be contrasted with conventional immediate release dosage forms in which the drug component is released into the gastrointestinal tract in a short period of time and the plasma drug levels peak shortly after administration. The design of conventional immediate release dosage forms is generally based on achieving the fastest possible rate of drug release and thus absorption, often at the risk of producing undesirable dose-related side effects. The sustained release dosage forms of certain embodiments seek to deliver a therapeutically effective amount of dexmethylphenidate to maintain the drug level in the plasma at a constant effective level to provide therapeutic benefit over a period of time, e.g., a 24 hour period. The sustained release dosage forms are designed to provide a rapid increase in the plasma concentration of the drug, which although can not remain constant, has a greater plasma drug concentration during work, school, such that the plasma concentration remains within the therapeutic range for a period of time, e.g., a 24 hour period. The terms controlled release, extended time release, and sustained release are interchangeable. Thus, the terms "modified release," "controlled release," "controlled release," "release rate controlled," "extended release," "extended time release," and "sustained release" can be used interchangeably herein. For the purposes of the discussion herein, the definition of the term "modified release" encompasses the scope of the definitions of the terms "extended release," "enhanced absorption," "controlled release," "sustained release," and "delayed release."

[0204] "Isolation layer," "sustained release coating layer I," and "sustained release coating layer II," as used herein, are defined in this application to mean a functional coating that includes at least one modified release polymer. Non-limiting examples of modified release polymers include pH independent polymers, pH dependent polymers (such as, for example, enteric or reverse enteric, soluble polymers, insoluble polymers, lipids, lipid materials, and combinations thereof. The controlled release coating, when coated onto a dosage form, can modify (e.g., slow) the rate of release of the active drug. For example, the controlled release coating can be designed such that when the coating is coated onto a dosage form, the dosage form in combination with the controlled release coating exhibits a "modified release," "controlled release," "sustained release," "extended release," and / or "delayed release" profile. Combinations thereof are permissible. The controlled release coating can optionally include additional materials that can alter the function of the controlled release coating. The term "modified release" is interchangeable with the terms "controlled release," "controlled release," and "rate controlled." The term "coating" is interchangeable with the term "coating layer."

[0205] The term "plasticizer" as used herein includes any compound capable of plasticizing or softening the polymer or binder used in the present application. The use of plasticizers is optional and can be included in the dosage form to modify the properties and characteristics of the polymer used in the coating or coatings or the core of the dosage form for convenient processing during the manufacture of the coating or coatings and / or the core of the dosage form. Once the coating or coatings and / or the core has been manufactured, certain plasticizers can function to increase the hydrophilicity of the coating or coatings and / or the core of the dosage form in the environment of use. The plasticizer can lower the melting temperature or glass transition temperature (softening point temperature) of the polymer or binder during the manufacture of the coating or coatings and / or the core. Plasticizers can be included with a polymer and lower its glass transition temperature or softening point. Plasticizers can also lower the viscosity of a polymer. Plasticizers can impart some particularly advantageous physical properties to the dosage forms of the present application.

[0206] The term "enteric coating" as used herein is defined to mean a coating or barrier applied to a dosage form, which coating or barrier layer can control the site of absorption of the active drug(s) in the digestive system. For example, an enteric coating can be used to: (i) protect the drug from the destructive effects of the enzymes or low pH environment of the stomach; (ii) prevent nausea or bleeding associated with irritation of the gastric mucosa by the drug; and / or (iii) deliver the drug in undiluted form in the intestine. Based on these criteria, in certain embodiments, the enteric coated dosage forms can be considered a type of delayed release dosage form. They are distinguished from sustained release dosage forms, which have a prolonged release of drug over a period of time to maintain therapeutic blood levels and reduce the incidence of side effects caused by rapid release; whereas with an enteric coating, the main goal is to limit the release of the drug to a predetermined region of the gastrointestinal tract. The enteric coating layer functions by the presence of a surface that is substantially stable at acidic pH, but ruptures at higher pH to allow release of the drug in the intestine.

[0207] The terms "core", "core I", and "core II" as used herein are defined to mean a solid carrier in which at least one active drug is homogeneously or non-homogeneously dispersed. The core can be formed by methods and materials well known in the art, such as, for example, by compression, fusion, or extrusion of the active drug with at least one pharmaceutically acceptable excipient. The core can be manufactured, for example, as a homogeneous or non-homogeneous unit tablet core, multiparticulate, or a plurality of microparticles compressed into a unit core. Non-limiting examples of cores include a microparticulate core, a matrix core, and an osmotic core. The core or cores can be coated with at least one functional coating and / or non-functional coating.

[0208] The terms "a," "an," or "at least one" are used interchangeably in the present application and are defined as "one" or "one or more" in the present application.

[0209] The present application encompasses any pharmaceutical comprising a pharmaceutically effective amount of dexmethylphenidate. This includes orally administrable pharmaceuticals. In particular, such pharmaceutical compositions include orally administrable modified release dosage forms comprising dexmethylphenidate. The dosage can conveniently be present in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts. A "solid dosage form" as used herein refers to a dosage form that is neither liquid nor gaseous. Such dosage forms include solid dosage forms such as tablets, powders, granules, capsules, suppositories, sachets, lozenges, troches. Capsule dosages comprise a solid composition within the solid capsule which can be made of gelatin or other conventional encapsulating materials.

[0210] For the purpose of clarity, technical solutions and advantages of the present application, the embodiments of the present application will be described in detail below. It should be noted that the embodiments in the present application and the features in the embodiments can be combined with each other arbitrarily without conflict.

[0211] The present application will be further described in detail below in combination with specific embodiments, but the embodiments should not be understood as limiting the present application.

[0212] The raw materials in the examples and comparative examples of the present application are all conventional market products.

[0213] Example 1: Preparation of sustained-release capsules containing two kinds of micro-tablets

[0214] 1 Preparation of blank cores

[0215] The prescription of the blank core is shown in Table 1:

[0216] Table 1

[0217]

[0218] Lactose, gum arabic and sodium alginate were mixed uniformly, and a micro 6 punch die with a diameter of 2-4 mm was selected to press tablets to obtain a tablet-shaped core.

[0219] After the Opadry coating premix was uniformly dispersed in purified water, the tablet-shaped core was isolated coated using a coating machine, and the coating weight was increased by 1-6% to obtain a blank core with an anti-abuse effect.

[0220] The blank core was evenly divided into blank core I and blank core II.

[0221] 2 Preparation of immediate release mini-tablets

[0222] The prescription is shown in Table 2:

[0223] Table 2

[0224]

[0225]

[0226] 2.1 Drug-containing layer I coating

[0227] Sufficiently stir dextromethylphenidate hydrochloride and povidone in water to obtain a clear first sustained-release drug solution, and put the blank core I into the coating machine, and coat with the prepared first sustained-release drug solution. After the coating machine is completely used, dry for about 20-120 min to obtain the microtablets of the blank core I coated with the drug-containing layer I, wherein the moisture content of the microtablets is not more than 5%.

[0228] 2.2 Sustained-release coating layer I coating

[0229] Disperse polyvinyl alcohol and Eudragit S100 uniformly in an aqueous ethanol solution, and coat the microtablets obtained in step 2.1 with the sustained-release coating layer I. After the coating is completed, dry for about 20-120 min to obtain the microtablets coated with the sustained-release coating layer I.

[0230] 2.3 Immediate-release layer coating

[0231] Sufficiently stir dextromethylphenidate hydrochloride and hydroxypropyl cellulose in water to obtain a clear immediate-release drug solution, and put the coated microtablets obtained in step 2.2 into the coating machine, and coat with the prepared immediate-release drug solution to obtain the sustained-release microtablets.

[0232] 3 Preparation of extended release mini-tablets

[0233] The prescription is shown in Table 3:

[0234] Table 3

[0235]

[0236] 3.1 Drug-containing layer II coating

[0237] Sufficiently stir dextromethylphenidate hydrochloride and povidone in water to obtain a clear second sustained-release drug solution, and put the blank core II into the coating machine, and coat with the prepared second sustained-release drug solution. After the coating machine is completely used, dry for about 20-120 min, and the moisture content of the microtablets is not more than 5%.

[0238] 3.2 Sustained-release coating layer II coating

[0239] Disperse polyvinyl alcohol and Eudragit FS 30D and RL 100 uniformly in an aqueous ethanol solution, and coat the microtablets obtained in step 3.1 with the sustained-release coating layer II. After the coating is completed, dry for about 30 min to obtain the individual sustained-release microtablets.

[0240] 4 Filling of capsules

[0241] The sustained-release microtablets and the sustained-release microtablets are filled in capsules at a weight ratio of 5:4 to obtain the target sample.

[0242] Example 2 Preparation of extended release capsules containing two types of mini-tablets

[0243] The prescription is shown in Table 4:

[0244] Table 4

[0245]

[0246]

[0247] Preparation method:

[0248] The preparation method of the capsule described in this example is similar to the preparation method described in Example 1, and the target sample is obtained after capsule filling.

[0249] Preparation of sustained-release capsules containing two kinds of microtablets in Example 3

[0250] The prescription is shown in Table 5:

[0251] Table 5

[0252]

[0253]

[0254] Preparation method:

[0255] The preparation method of the capsule described in this example is similar to the preparation method described in Example 1, and the target sample is obtained after capsule filling.

[0256] Preparation of sustained-release capsules containing two kinds of microtablets in Example 4

[0257] 1 Preparation of blank cores

[0258] The prescription is shown in Table 6:

[0259] Table 6

[0260]

[0261] After the dextrin, xanthan gum, sodium alginate and β-cyclodextrin are uniformly mixed, the hydroxypropyl cellulose solution is used as the binder to prepare the pellet core by the extrusion-spheronization method. The separating layer accessories hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyethylene glycol and titanium dioxide are uniformly dispersed in purified water, and the fluidized bed is used to separate and coat the blank pellet core, and the coating weight is increased by 1-6%, to obtain a blank core with anti-abuse effect.

[0262] The blank core is evenly divided into blank core I and blank core II.

[0263] 2 Preparation of immediate release mini-pellets

[0264] The prescription of the sustained-release pellets is shown in Table 7:

[0265] Table 7

[0266]

[0267] 2.1 Drug-containing layer I coating

[0268] The dextromethylphenidate hydrochloride and hypromellose are fully stirred in water to obtain a clear first sustained-release drug solution, and the blank core I is put into the fluidized bed and coated with the prepared first sustained-release drug solution. After the entire coating is completed, drying is performed for about 20-120 min, and the moisture content of the pellets is not more than 5%.

[0269] 2.2 Sustained-release coating layer I coating

[0270] The Eudragit L 30D-55, polyethylene glycol, titanium dioxide, and talc powder are uniformly dispersed in an aqueous ethanol solution, and the pellets obtained in step 2.1 are coated with the sustained-release coating solution. After the coating is completed, drying is performed for about 20-120 min, and the coated pellets are obtained.

[0271] 2.3 Immediate-release layer coating

[0272] The dextromethylphenidate hydrochloride and hypromellose are fully stirred in water to obtain a clear immediate-release drug solution, and the coated pellets obtained in step 2.2 are put into the fluidized bed and coated with the prepared immediate-release drug solution, and the sustained-release pellets are obtained.

[0273] 3 Preparation of extended release mini-pellets

[0274] The prescription is shown in Table 8:

[0275] Table 8

[0276]

[0277] 3.1 Drug-containing layer II coating

[0278] The dextromethylphenidate hydrochloride and hypromellose are fully stirred in water to obtain a clear second sustained-release drug solution, and the blank core II is put into the fluidized bed and coated with the prepared second sustained-release drug solution. After the entire coating is completed, drying is performed for about 20-120 min, and the moisture content of the pellets is not more than 5%.

[0279] 3.2 Sustained-release coating layer II coating

[0280] The Eudragit L 30D-55, Eudragit RS 30D triethyl citrate and talc are dispersed uniformly in an aqueous ethanol solution, and the sustained-release pellets obtained in step 3.1 are coated, and after the coating is completed, the pellets are dried for about 20-120 min to obtain the target sample.

[0281] 4 Filling of capsules

[0282] The sustained-release pellets and the sustained-release pellets are filled into capsules at a weight ratio of 3:5 to obtain the target sample.

[0283] Example 5 Preparation of sustained-release capsules containing two kinds of pellets

[0284] The prescription is shown in Table 9:

[0285] Table 9

[0286]

[0287]

[0288] Preparation method:

[0289] The preparation method of the capsules described in this example is similar to the preparation method described in Example 4, and the target sample is obtained after the capsules are filled.

[0290] Example 6 Preparation of sustained-release capsules containing two kinds of pellets

[0291] The prescription is shown in Table 10:

[0292] Table 10

[0293]

[0294]

[0295] Preparation method:

[0296] The preparation method of the capsules described in this example is similar to the preparation method described in Example 4, and the target sample is obtained after the capsules are filled.

[0297] Example 7 Preparation of sustained-release capsules containing two kinds of pellets

[0298] The prescription is shown in Table 11:

[0299] Table 11

[0300]

[0301] Preparation method:

[0302] The preparation method of the capsules described in this example is similar to the preparation method described in Example 4, and the target sample is obtained after the capsules are filled.

[0303] 1 Blank cores

[0304] The blank core can be prepared by mixing sucrose, microcrystalline cellulose, starch, mannitol, lactose or the like in one or more combinations and uniformly pressing the mixture into a tablet. The particle size of the single blank core tablet can be passed through a 35-80 mesh sieve (355-212 um), and the weight of 5000 blank cores is 5-10 mg.

[0305] The blank cores are evenly divided into blank core I, blank core II and blank core III.

[0306] 2 Preparation of immediate release mini-tablets, first extended release mini-tablets and second extended release mini-tablets

[0307] The prescription is shown in Table 12:

[0308] Table 12

[0309]

[0310] First, the dextromethylphenidate hydrochloride and povidone in the prescription are prepared into a solution, then the blank core I is put into the fluidized bed, coated with the prepared drug-containing solution, and dried for about 20-120 min, so that the moisture is not more than 5%, to obtain the immediate-release microtablet.

[0311] Similarly, after the drug-containing solution is sprayed on the blank core II and the blank core III, the remaining sustained-release materials are prepared into an ethanol-water solution dispersion, and then sustained-release coating is performed to obtain the first sustained-release microtablet and the second sustained-release microtablet.

[0312] The capsule is prepared by weighing and filling the drugs in a ratio of 11.48%:42.8%:45.71%.

[0313] Preparation of the capsule containing three pellets in Comparative Example 2

[0314] 1 Preparation of blank cores

[0315] The blank core can be prepared by mixing sucrose, microcrystalline cellulose, starch, mannitol, lactose or the like in one or more combinations and uniformly pressing the mixture into a tablet. The particle size of the single blank core tablet can be passed through a 35-80 mesh sieve (355-212 um), and the weight of 5000 blank cores is 5-10 mg.

[0316] The blank cores are evenly divided into blank core I, blank core II and blank core III.

[0317] 2 Preparation of immediate release mini-pellets, first extended release mini-pellets and second extended release mini-pellets

[0318] The prescription is shown in Table 13:

[0319] Table 13

[0320]

[0321] Preparation method:

[0322] First, the salt of lisdexamfetamine hydrochloride in the prescription, hydroxypropyl cellulose is prepared into a solution, and then the blank core I is put into the fluidized bed, and the prepared drug-containing solution is coated, and dried for about 20-120 min, and the moisture is not more than 5%, and the immediate-release pellets are obtained.

[0323] Similarly, first, the mixed solution of lisdexamfetamine hydrochloride and polyvinyl alcohol is prepared according to the prescription, and then the remaining sustained-release material is prepared into an ethanol-water solution dispersion after the drug-containing solution is sprayed on the blank core II and the blank core III respectively, and then the first sustained-release pellets and the second sustained-release pellets are obtained.

[0324] The capsule is weighed and filled with the drug in the ratio of 22.20%:41.01%:36.79%, and the target sample is obtained.

[0325] Test example 1 batch uniformity test

[0326] The release experiment of the application: the sample is first released in 0.01 mol / L hydrochloric acid solution for 0-2 hours, and then transferred to pH 6.8 phosphate buffer for 2-16 hours, the medium volume is 500 ml, and the basket method is used for dissolution test, wherein the rotation speed is 100 rpm.

[0327] Table 14: Batch uniformity test

[0328]

[0329]

[0330] Conclusion: when the three kinds of micro-pellets in Comparative Example 1 are filled in one capsule, the RSD values of 6 capsules are significantly different, indicating that the batch difference is large (see Figure 1 ). While the two kinds of micro-pellets in Example 1 of the application are filled in one capsule, the RSD values at all time points are within 5%, and the batch difference is small (see Figure 2 ).

[0331] The RSD values of the three-micro-pellet-filled capsules prepared in Comparative Example 2 are all more than 10% within 10h, and the batch difference is obvious. While the capsules prepared in Example 5 of the application, the RSD values at all time points are within 5%, and the batch difference is small.

[0332] Test example 2 dissolution test

[0333] The release experiment of the present application: the sample is first released in 0.01 mol / L hydrochloric acid solution for 0-2 hours, and then transferred to pH 6.8 phosphate buffer for 2-16 hours, the medium volume is 500 ml, the basket method, the rotation speed is 100 rpm.

[0334] Table 15: Dissolution test

[0335]

[0336] It can be seen from Table 15 and Figure 3 It can be seen from Table 15 and

[0337] The drug in Comparative Examples 1 and 2 is continuously released and accumulated after 0.5 hours, indicating that the three micro-tablets interfere with each other during the release process, and the release platform is basically reached at 8 hours, and does not show a three-pulse release trend.

[0338] Test Example 3: In vivo drug concentration-time change

[0339] To evaluate the drug concentration in vivo after administration, using dextroamphetamine hydrochloride as a model drug, the drug concentration change in mice was determined. The samples of Example 1, Example 5, Comparative Example 1 and Comparative Example 2 were administered to mice, and blood was collected at different time points within 24 hours, and the concentration of dextroamphetamine hydrochloride in plasma was detected. The results are shown in Figure 4

[0340] Figure 4 The results of the in vivo drug concentration-time of Example 1, Example 5, Comparative Example 1 and Comparative Example 2 samples. The in vivo blood drug concentration results also show that the drug of the present application also shows a three-pulse release over time in vivo, indicating that the content of the present application can achieve precise timed release. And the drug of the present application decreases more gently after 12 hours (see Figure 4 ), to a certain extent, it can avoid withdrawal symptoms, and prolong the drug effect, suggesting that the future clinical administration of the present application can reduce the withdrawal symptoms of patients due to the decrease of drug effect.

[0341] Test Example 4: Abuse prevention study

[0342] ​Methylphenidate hydrochloride and dexmethylphenidate hydrochloride are respiratory stimulants. Small doses of methylphenidate hydrochloride and dexmethylphenidate hydrochloride stimulate the respiratory center through the carotid body chemoreceptor reflex, and large doses of methylphenidate hydrochloride and dexmethylphenidate hydrochloride can directly stimulate the medulla oblongata respiratory center. Methylphenidate hydrochloride and dexmethylphenidate hydrochloride belong to the first category of psychotropic substances, are managed equally with anesthetics, and are special management drugs. If methylphenidate hydrochloride and dexmethylphenidate hydrochloride are used in large quantities without a doctor's order, they are easy to cause stimulant abuse. The present application refers to the Technical Guidelines for Pharmaceutical Research on Abuse Prevention of Opioid Oral Solid Generic Drugs issued by the Drug Review Center of the State Drug Administration to evaluate the abuse prevention of the application examples and the comparative examples by nasal inhalation.

[0343] About 50 g of the capsule contents were crushed with a grinder (12000 rpm) for 5 min, and the crushed particles were sieved through 1000 μm and 500 μm sieves. The sieved and unsieved particles were weighed, and the proportion of particles of different sizes was calculated. The test results are shown in Table 16:

[0344] Table 16

[0345]

[0346]

[0347] Nasal absorption evaluation: In combination with the characteristics of nasal inhalation administration and common pharmaceutical technologies, the pharmaceutical evaluation index for nasal inhalation abuse should include the particle size and weight of the nasal inhalation particles. The mass percentage of fine particles <500 μm can reflect the bioavailability of nasal inhalation abuse to some extent. Under the same operation conditions, the mass percentage of fine particles <500 μm of the application examples 1 to 7 is less than 10%, which indicates that the application is more resistant to crushing than the comparative examples, and is not easy to cause stimulant abuse through nasal inhalation.

[0348] The proportion of fine particles <500 μm in the comparative example 1 and the comparative example 2 is large, about 80%, which is more likely to cause stimulant abuse through nasal inhalation extraction.

[0349] Although the embodiments of the present application have been shown and described above, it should be understood that the above embodiments are exemplary and should not be construed as limiting the present application, and those skilled in the art can make changes, modifications, replacements and variations to the above embodiments within the scope of the present application.

Claims

1. A sustained-release composition formulation comprising sustained-release microparticles and extended-release microparticles: wherein: The slow-release microparticles include a blank core I and a slow-release layer I and a fast-release layer sequentially disposed outside the blank core I; The sustained-release microparticles include a blank core II and a sustained-release layer II disposed outside the blank core II; The immediate-release layer, sustained-release layer I, and sustained-release layer II all contain active ingredients, including methylphenidate, stereoisomers of methylphenidate, or pharmaceutically acceptable salts thereof.

2. The sustained-release composition formulation according to claim 1, wherein, The weight ratio of the slow-release microparticles to the total slow-release microparticles is 0.5:1 to 1.5:1; Optionally, in the sustained-release composition formulation, the active ingredient is dextromethorphan hydrochloride; Optionally, the total content of the active ingredient is 5-80 mg.

3. The sustained-release composition formulation according to claim 1 or 2, wherein, The blank core I and the blank core II each include a core body, and the surface of the core body is further covered with a blank isolation layer; and / or Based on the total weight of the core, the core contains 30%-80% filler, 20%-70% anti-abuse additives, and optionally, adhesives and / or lubricants.

4. The sustained-release composition formulation according to claim 1 or 2, wherein, The sustained-release layer I includes a drug-containing layer I and a sustained-release coating layer I; the sustained-release layer II includes a drug-containing layer II and a sustained-release coating layer II; the immediate-release layer, the drug-containing layer I, and the drug-containing layer II each contain the active ingredient.

5. The sustained-release composition formulation according to claim 4, wherein, The immediate-release layer comprises a first dose of the active ingredient, a binder, and optionally a disintegrant; and / or The drug-containing layer I contains a second dose of the active ingredient and a binder; and / or The drug-containing layer II contains a third dose of the active ingredient and a binder.

6. The sustained-release composition formulation according to claim 5, wherein, In the immediate-release layer, the content of the adhesive is 1.00%-30% based on the total weight of the immediate-release layer; or the content of the adhesive is 1.00%-30% based on the total weight of the immediate-release layer, and the content of the disintegrant is 5%-40%.

7. The sustained-release composition formulation according to claim 5, wherein, In the drug-containing layer I, the adhesive content is 1%-30% based on the total weight of the drug-containing layer I; and / or In the drug-containing layer II, the content of the adhesive is 1%-65% based on the total weight of the drug-containing layer II.

8. The sustained-release composition formulation according to claim 5, wherein, The active ingredient in the immediate-release layer accounts for 30%-40% of the total weight of the active ingredients, the active ingredient in drug-containing layer I accounts for 35%-50% of the total weight of the active ingredients, and the active ingredient in drug-containing layer II accounts for 10%-35% of the total weight of the active ingredients; or The active ingredient in the immediate-release layer accounts for 35% of the total weight of the active ingredients, the active ingredient in drug-containing layer I accounts for 35% of the total weight of the active ingredients, and the active ingredient in drug-containing layer II accounts for 30% of the total weight of the active ingredients; or The immediate-release layer contains 35% of the total active ingredient by weight, the drug-containing layer I contains 40% of the total active ingredient by weight, and the drug-containing layer II contains 25% of the total active ingredient by weight; or The immediate-release layer contains 32% of the total active ingredient by weight, the drug-containing layer I contains 50% of the total active ingredient by weight, and the drug-containing layer II contains 18% of the total active ingredient by weight; or The immediate-release layer contains 30% of the total active ingredient by weight, the drug-containing layer I contains 50% of the total active ingredient by weight, and the drug-containing layer II contains 20% of the total active ingredient by weight; or The active ingredient in the immediate-release layer accounts for 40% of the total weight of the active ingredients, the active ingredient in drug-containing layer I accounts for 40% of the total weight of the active ingredients, and the active ingredient in drug-containing layer II accounts for 20% of the total weight of the active ingredients.

9. The sustained-release composition formulation according to claim 4, wherein, The sustained-release coating layer I and the sustained-release coating layer II respectively comprise an enteric coating material and a plasticizer, and optionally contain one or more of an anti-adhesive agent and a light-blocking agent; and / or Based on the total weight of the sustained-release coating layer I or the sustained-release coating layer II, the content of the enteric coating material is 20%-98%, and the content of the plasticizer is 2%-80%.

10. The sustained-release composition formulation according to claim 3, 5, or 9, wherein, The filler is selected from one or more of compressible starch, powdered sugar, dextrin, calcium sulfate, lactose, mannitol, sorbitol, dextrin, or microcrystalline cellulose; and / or The anti-abuse excipients are selected from one or more of the following: gum arabic, xanthan gum, pectin, carrageenan, gelatin, guar gum, tragacanth gum, agar, alginate, sodium alginate, propylene glycol alginate, polyoxyethylene, carbomer, β-cyclodextrin, hydroxypropyl starch, hydroxyethyl starch, chitosan, or polyvinylpyrrolidone; and / or The lubricant is selected from one or more of sodium stearate fumarate, talc, stearic acid, and magnesium stearate; and / or The adhesive is selected from one or more of starch paste, polyethylene glycol-4000, polyethylene glycol-6000, polyvinyl alcohol, methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethylcellulose, povidone, and polyvinylpyrrolidone; and / or The disintegrant is selected from one or more of the following: dry starch, croscarmellose, croscarmellose sodium carboxymethyl cellulose, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose; and / or The enteric coating material is selected from one or more of the following: methacrylic acid copolymer, aminomethacrylic acid copolymer, hydroxypropyl methylcellulose phthalate, cellulose acetate, and hydroxypropyl methylcellulose acetate succinate; and / or The plasticizer is selected from one or more of propylene glycol, glycerin, polyethylene glycol, castor oil, diethyl phthalate, triethyl citrate, tributyl acetylacetonate, and polyvinyl alcohol; and / or The anti-adhesion agent is selected from one or more of talc, stearic acid micronized silica gel; and / or The light-blocking agent is selected from one or more of titanium dioxide, zinc oxide, calcium carbonate, and talc; and / or The blank isolation layer contains one or more pharmaceutical excipients selected from the Opadry-White series, Opadry-Transparent series, Opadry II series, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, polyethylene glycol, titanium dioxide, and talc.

11. The sustained-release composition formulation according to claim 1 or 2, wherein, The sustained-release composition formulation is administered orally directly in microparticle form or in capsules. and / or The sustained-release composition is a sustained-release capsule containing dextromethorphan hydrochloride, the capsule containing two types of microparticles; or the sustained-release composition is a sustained-release capsule containing dextromethorphan hydrochloride, the capsule containing two types of microtablets.

12. A method for preparing a sustained-release composition formulation according to any one of claims 1-11, wherein the sustained-release composition formulation is a sustained-release capsule containing dextromethorphan hydrochloride, the capsule containing two types of microplates, the method comprising: (1) Preparation of blank core I and blank core II The core materials of blank core I and blank core II are mixed evenly and then compressed into tablets to obtain a tablet core. After the blank isolation layer material is evenly dispersed in water, the sheet-like cores of blank core I and blank core II are isolated and coated using a coating machine to obtain blank core I and blank core II respectively. (2) Preparation of slow-release microplates The raw materials of drug-containing layer I, sustained-release coating layer I and immediate-release layer are dispersed evenly in water or ethanol aqueous solution to obtain drug solution of drug-containing layer I, drug solution of sustained-release coating layer I and drug solution of immediate-release layer. Using a coating machine, the blank core I is coated sequentially with drug-containing layer I solution, sustained-release coating layer I solution, and immediate-release layer solution, and then dried to obtain a sustained-release microtablet. (3) Preparation of sustained-release microplates The raw materials containing drug layer II and sustained-release coating layer II are evenly dispersed in water or ethanol aqueous solution to obtain drug solution containing drug layer II and sustained-release coating layer II. Using a coating machine, the blank core II is coated sequentially with drug-containing layer II solution and sustained-release coating layer II solution and then dried; Obtain sustained-release microplates; (4) Capsule filling The sustained-release microplates and the slow-release microplates are then encapsulated to obtain the final product.

13. A method for preparing a sustained-release composition formulation according to any one of claims 1-11, wherein the sustained-release composition formulation is a sustained-release capsule containing dextromethorphan hydrochloride, the capsule containing two types of microparticles, the method comprising: (1) Preparation of blank core I and blank core II The core materials of blank core I and blank core II are mixed evenly and then extruded to prepare pellet-shaped cores; After the blank isolation layer material is evenly dispersed in water, the pellet cores of blank core I and blank core II are isolated and coated using a fluidized bed to obtain blank core I and blank core II. (2) Preparation of sustained-release microcapsules The raw materials of drug-containing layer I, sustained-release coating layer I and immediate-release layer are dispersed evenly in water or ethanol aqueous solution to obtain drug solution of drug-containing layer I, drug solution of sustained-release coating layer I and drug solution of immediate-release layer. The blank core I was coated and dried using a fluidized bed and sequentially with drug-containing layer I solution, sustained-release coating layer I solution, and immediate-release layer solution. Slow-release microparticles were obtained; (3) Preparation of sustained-release microcapsules The raw materials containing drug layer II and sustained-release coating layer II are evenly dispersed in water or ethanol aqueous solution to obtain drug solution containing drug layer II and sustained-release coating layer II. The blank core II was coated and dried using a fluidized bed and sequentially with drug-containing layer II solution and sustained-release coating layer II solution. Sustained-release microgranules were obtained; (4) Capsule filling The sustained-release microspheres and the slow-release microspheres are then encapsulated to obtain the final product.

14. Use of a sustained-release or controlled-release composition formulation according to any one of claims 1-11, or a sustained-release or controlled-release composition formulation prepared according to the preparation method of claim 12, or a sustained-release or controlled-release composition formulation prepared according to the preparation method of claim 13, in the preparation of a medicament for treating mental illness, wherein, The mental illness mentioned is attention deficit hyperactivity disorder.

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