A sustained release pharmaceutical composition and a method for preparing the same

Abstract

The present application relates to a sustained-release pharmaceutical composition and a preparation method thereof, which is a double-layer tablet including a floating layer and a drug-containing layer, wherein the floating layer includes a floating material, and continuously floats and releases the drug in the stomach. The preparation method of the sustained-release pharmaceutical composition of the present application is simple, suitable for industrial scale-up production, and the sustained-release pharmaceutical composition of the present application can prolong the gastric retention time of the drug, thereby prolonging the drug action time, improving the drug safety and patient compliance.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparations, and specifically to a sustained-release pharmaceutical composition and its preparation method. Background Technology

[0002] In recent years, with the rapid development of the pharmaceutical industry, novel drug delivery systems have been one of the main directions of pharmaceutical development, among which sustained-release and controlled-release formulations have been extensively studied. Sustained-release and controlled-release formulations can maintain drug concentrations within the effective concentration range for extended periods. They are ideally suited for drugs requiring frequent dosing or with a narrow therapeutic window. Compared to conventional formulations, sustained-release formulations reduce dosing frequency and can significantly increase patient compliance or reduce drug side effects.

[0003] Despite the significant advancements in sustained-release formulation technology, the development of sustained-release formulations of active pharmaceutical ingredients remains a major challenge. Many known sustained-release technologies utilize a carrier matrix, which provides some degree of control over the effective delivery level of the active drug. However, the physiological state of the patient—whether they have eaten and their stomach is emptying—still influences the therapeutic efficacy of the drug.

[0004] For example, in the absence of food intake, the dosage form empties from the stomach into the small intestine, a process that lasts only 2-4 hours. The dosage form then travels through the small intestine to the colon. By the time it reaches the colon, the drug has not yet been released from its sustained-release formulation. This is particularly disadvantageous for drugs that are primarily absorbed in the stomach and small intestine. Furthermore, some drugs are pH-dependent, meaning their solubility decreases as pH increases. Due to the slow release before reaching the colon, less of these drugs are released, and the undissolved drug may not be fully absorbed.

[0005] Gastric flotation formulations are a type of sustained-release formulation. They can retain drugs in the stomach for a longer period of time, prolonging the release time of drugs throughout the gastrointestinal tract, improving drug absorption, and thus increasing drug bioavailability. They are currently a research hotspot in sustained-release formulations.

[0006] Most gastric flotation tablets reported in existing literature require a floating time, meaning that the tablet itself cannot float immediately upon contact with water (or gastric juice). This floating time is usually more than ten minutes, which poses a potential risk that the tablet may be expelled from the pylorus into the intestine before it can float, thus losing its gastric flotation effect. Summary of the Invention

[0007] The purpose of this invention is to overcome the shortcomings of the prior art and provide a sustained-release drug composition and its preparation method. The composition can float rapidly in gastric juice, has the characteristics of long continuous floating time and slow drug release, and the preparation method is simple and the production process is stable, making it suitable for industrial-scale production.

[0008] The objective of this invention is achieved through the following technical solution:

[0009] The sustained-release pharmaceutical composition of the present invention is a bilayer tablet comprising a floating layer and a drug-containing layer, wherein the floating layer comprises a floating material that continuously floats in the stomach and releases the drug.

[0010] The addition of buoyancy materials gives the drug composition the ability to float, allowing the drug to remain in the stomach.

[0011] In this invention, the floating material comprises one or more of hydrophobic esters, higher fatty alcohols, cellulose, vinyl polymers, or propylene polymers; preferably, when the floating material is selected from vinyl polymers, it is preferably one or more of vinyl acetate, povidone, vinyl acetate-based copolymers, and vinylpyrrolidone-based copolymers; when the floating material is selected from propylene polymers, it is preferably one or more of polymethacrylate, methyl methacrylate, ethyl acrylate, butyl acrylate, or tert-butyl acrylate; or, when the floating material is selected from higher fatty alcohols, it is preferably C6-C. 30 fatty alcohols, preferably C 10 -C 20 Fatty alcohols, more preferably one or more of lauryl alcohol, tetradecyl alcohol, hexadecyl alcohol, octadecyl alcohol, eicosanool, docosanool or octadecyl alcohol; more preferably octadecyl alcohol; or, when the floating material is selected from cellulose, one or more of hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, and hydroxypropyl cellulose are preferred.

[0012] In this invention, the inventors discovered that when the floating material is selected from vinyl polymers, it can provide excellent structural integrity and good flocculation properties for the pharmaceutical composition, which helps to control or prolong the drug release rate and other effects. Preferably, it comprises at least one of polyvinyl acetate or povidone; more preferably, it comprises a mixture of polyvinyl acetate and povidone.

[0013] In this invention, the polyvinyl acetate (PVAc) in the polyvinyl acetate-polyvinyl ketone mixture is a homopolymer of vinyl acetate, with a molecular weight (Mw) typically around 1 × 10⁻⁶. 5 To approximately 1×10 6 Polyvinylpyrrolidone (PVP) is a homopolymer of 1-vinylpyrrolidone-2-one, with a molecular weight (Mw) typically around 1 × 10⁻⁶. 3 To approximately 1×10 7 Approximately 2.5 × 10 3 Approximately 3×10 6 Or approximately 1×10 4 To approximately 1×10 5 .

[0014] In this invention, based on the total weight of polyvinyl acetate and povidone, the floating material may comprise approximately 10–90% polyvinyl acetate by weight, approximately 30–90% polyvinyl acetate by weight, approximately 50–90% polyvinyl acetate by weight, approximately 70–90% polyvinyl acetate by weight, or approximately 80–90% polyvinyl acetate by weight. Available floating materials include commercially available products from BASF, a mixture of polyvinyl acetate and povidone in an 80:19 ratio, marketed as Kollidon SR. The polyvinyl acetate-povidone mixture in the embodiments of this invention is such a mixture of polyvinyl acetate and povidone in an 80:19 ratio.

[0015] In this invention, the weight percentage of the floating material, based on the total weight of the prescription, is 5-60%, 10-50%, 15%-40%, 20-40%, 20-35%, or 25-35%, preferably 10-50%; more preferably 15%-40%; further preferably 20-35%; and most preferably 25-35%.

[0016] The sustained-release pharmaceutical composition of the present invention also includes a sustained-release material.

[0017] In a preferred embodiment of the present invention, the sustained-release material is selected from one or more of cellulose, synthetic polymers, fats, waxes, or natural gums; preferably, when the sustained-release material is selected from cellulose, water-soluble cellulose is preferred, and more preferably one or more of hydroxypropyl cellulose, methylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, or hydroxymethyl cellulose; when the sustained-release material is selected from synthetic polymers, one or more of povidone, vinyl acetate, polyvinyl alcohol, polyoxyethylene, or polymethacrylate resins are preferred; when the sustained-release material is selected from fats, one or more of soybean oil, ethyl oleate, cocoa butter, glyceryl tristearate, hydrogenated castor oil, or glyceryl monostearate are preferred; when the sustained-release material is selected from waxes, one or more of beeswax, carnauba wax, white wax, paraffin wax, lanolin wax, or insect wax are preferred; when the sustained-release material is selected from natural gums, one or more of sodium alginate, agar, tragacanth gum, xanthan gum, or locust bean gum are preferred.

[0018] In a preferred embodiment of the present invention, the sustained-release material is selected from hydroxypropyl methylcellulose.

[0019] Hydroxypropyl methylcellulose (HPMC) is a commonly used hydrophilic sustained-release matrix material. It possesses different molecular weights and viscosities, ranging from 3 mPa·s to 100,000 mPa·s. Specific types include HPMC E3, HPMC E5, HPMC E15, HPMCK100LV, HPMC K100M, HPMC K4M, HPMC K15M, HPMC A4M, and HPMC A4C, with HPMC K100LV being preferred. In this invention, the hydroxypropyl methylcellulose with a viscosity range of 50 mPa·s to 500 mPa·s is preferably used; more preferably, the selected hydroxypropyl methylcellulose is a single-viscosity hydroxypropyl methylcellulose or a composition of hydroxypropyl methylcellulose with different viscosities.

[0020] In this invention, the weight percentage of the sustained-release material, based on the total weight of the prescription, is 1-30%, preferably 1-20%; more preferably 1-16%; further preferably 1-12%; even more preferably 1-8%; and most preferably 1-6%.

[0021] In this invention, the weight percentage of the drug, based on the total weight of the prescription, is 1-40%, 5-40%, 5-35%, 10-35%, 20-35%, 1-30%, 1-20%, 1-15%, or 5-15%; preferably 1-40%; more preferably 1-30%; further preferably 1-20%; even more preferably 1-15%; and still even more preferably 5-15%.

[0022] Preferably, the drug includes drugs that act locally in the stomach, drugs that are mainly absorbed in the stomach, drugs that are poorly soluble in alkaline pH, drugs that are unstable in the intestine, drugs that degrade in the colon, drugs with a narrow absorption window, or other drugs suitable for being prepared for gastric retention; including, deoxyephedrine hydrochloride, benzphenamine hydrochloride, isoproterenol sulfate, benzomorpholine hydrochloride, carbamoyl methylcholine chloride, metformin, methylphenidate hydrochloride, cholineophylline, cephalexin hydrochloride, difenidol, meclomethasone hydrochloride, prochlorperazine maleate, phenoxybenzamine, thiophenepazine maleate, indanedione, phenylindanedione erythritol tetranitrate, digoxin, isoflurane, meperazine disulfate, ferrous sulfate, salbutamol, aminocaproic acid, mecaminide hydrochloride, procainamide hydrochloride, amphetamine sulfate, acetazolamide, nifedipine. Acetazolamide, benzylfluthiazide, chlorpropamide, glipizide, glibenclamide, gliclazide, tolbutamide, chlorpropamide, sulfadiazine, traglitazone, orlistat, bupropion, naphazoline, sulfadiazine, chlormadinone, finasteride, captopril, cefotaxime, hydrochlorothiazide, ranitidine, flurbiprofen, fenbufen, fluprofen, tomatine, alclofenac, mefenoxuron, methylphenidate Naphazoline, flufenamic acid, nimodipine, nifedipine, nisodipine, nicardipine, felodipine, lidocaine, tipamipro, galopamipro, amlodipine, mirtazapine, lisinopril, enalapril, captopril, ramipril, enalapril, famotidine, nizatidine, sucralfate, propytonin, nilotinib, rivaroxaban, lenalidomide, lurasidone, ziprasidone, or pharmaceutically acceptable salts thereof;

[0023] Salts include, but are not limited to, acid addition salts and base addition salts, including hemisalts. Commonly used pharmaceutical salts include non-toxic salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, and hydrofluoric acid; and non-toxic salts derived from organic acids including aliphatic mono- and dicarboxylic acids, phenyl-substituted alkyl acids, aromatic acids, and aliphatic acids. Potentially useful salts include acetates, aspartates, benzoates, methylbenzoates, citrates, oxalates, fumarates, lactates, malates, maleates, malonic acid, methanesulfonates, stearates, etc.

[0024] Preferably, the drug is selected from drugs that are poorly soluble in alkaline pH values, more preferably drugs that are readily soluble in the stomach, further preferably lurasidone or a pharmaceutically acceptable salt thereof; even more preferably lurasidone hydrochloride;

[0025] Preferably, each unit dose of the sustained-release pharmaceutical composition contains 1-500 mg, 5-400 mg, 5-300 mg, 5-200 mg, 5-150 mg, 5-120 mg, 10-100 mg, or 20-80 mg of active ingredient;

[0026] When the active ingredient is lurasidone hydrochloride, each unit dose of the sustained-release composition preferably contains 5 to 200 mg of the active ingredient, more preferably 10 to 150 mg of lurasidone hydrochloride. Specifically, each unit dose of the sustained-release composition may contain 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, or 150 mg of lurasidone hydrochloride. More preferably, each unit dose of the sustained-release composition contains 20 mg, 40 mg, 60 mg, 80 mg, or 120 mg of lurasidone hydrochloride.

[0027] In this invention, the pharmaceutical composition may also contain other pharmaceutically acceptable excipients required for production. Pharmaceutically acceptable excipients can be any component that has no adverse effect on the formulation and is necessary to combine with it, including, for example, fillers, binders, disintegrants, lubricants, wetting agents, adhesives, gas-generating agents, surfactants, etc.

[0028] During mixing, granulation, and tableting, fillers not only increase the weight (or volume) of tablets but also improve material flowability and compressibility, and enhance content uniformity. Typical fillers include mannitol, lactose, xylitol, sorbitol, dicalcium phosphate, calcium carbonate, pregelatinized starch, microcrystalline cellulose, dextrin, or other pharmaceutically commonly used fillers; lactose is preferred; combinations of lactose with other fillers are more preferred, such as combinations of lactose and microcrystalline cellulose, lactose and pregelatinized starch, lactose and mannitol, etc.; combinations of lactose and microcrystalline cellulose are even more preferred.

[0029] Preferably, the filler weight percentage is 0-40%, 0-30%, 1-40%, 5-30%, 10-25%, 8-25%, or 15-25% based on the total weight of the prescription; preferably, it is 1-40%; more preferably 5-30%, more preferably 8-25%, and even more preferably 15-25%.

[0030] In this invention, when the filler is selected from a composition of lactose and microcrystalline cellulose, the weight percentage of lactose is 1-30%, preferably 1-20%, more preferably 5-20%, and even more preferably 12-20%, based on the total weight of the formulation; the weight percentage of microcrystalline cellulose is 1-20%, preferably 1-15%, more preferably 1-10%, and even more preferably 3-8%, based on the total weight of the drug-containing layer.

[0031] In this invention, when the filler is selected from a composition of lactose and microcrystalline cellulose, the weight percentage of lactose and microcrystalline cellulose is 10:1 to 1:5, preferably 10:1 to 1:1, more preferably 7:1 to 1:1, further preferably 5:1 to 1:1, even more preferably 4:1 to 2:1, and most preferably 3:1.

[0032] In this invention, the inventors discovered that an adhesive can also be added to the prescription. The adhesive has a bioadhesive effect, which can make the drug adhere to the gastric mucosa and prolong the drug's retention time in the stomach.

[0033] Adhesives can be of various types, including synthetic and natural sources, such as gelatin, pectin, astragalus gum, gum arabic, sodium alginate, polyoxyethylene, carbomer, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, polyvinyl alcohol, polycarboxylate, polyaspartic acid, polyglutamic acid, polyvinyl sulfate, hyaluronic acid, or polysaccharides, with carbomer being the preferred choice.

[0034] Carbomer is a synthetic polymer of acrylic acid and allyl sucrose or crosslinked with allyl pentaerythritol ether. On a dry basis, it contains approximately 56% to 68% carboxyl groups, and its molecular weight (Mw) is theoretically estimated to be around 7 × 10⁻⁶. 5 Approximately 4×10 6 When in contact with water, carbomer forms a viscous substance through osmosis, polymer hydration, and expansion, which can delay the dissolution of the gel skeleton and drug diffusion, while also prolonging the floating time.

[0035] In this invention, the adhesive can be one, two or more adhesives in combination, preferably a combination containing carbomer, and more preferably a combination of polyethylene oxide and carbomer.

[0036] Polyoxyethylene is a nonionic homopolymer of ethylene oxide, and its molecular weight (Mw) is typically 1 × 10⁻⁶. 5 Approximately 7×10 6 It is a viscous polymer. When in contact with water, polyethylene oxide rapidly hydrates to form a gel layer on the wetted tablet surface, delaying drug release through swelling and adhesion of its hydrophilic skeleton. Combined with carbomer, it provides even better adhesion.

[0037] Preferably, the weight percentage of the adhesive, based on the total weight of the prescription, can be 0-50%, 0-40%, 1-50%, 1-45%, 5-40%, 10-35%, 15-35%, 20-30%, or 5-25%; preferably, it is 1-50%; more preferably, it is 5-40%; more preferably, it is 10-35%; even more preferably, it is 15-35%; and most preferably, it is 20-30%.

[0038] In this invention, when the adhesive uses a combination of polyethylene oxide and carbomer, the weight percentage of polyethylene oxide is 1-40% based on the total weight of the formulation; preferably 5-30%; more preferably 10-25%; and even more preferably 15-25%.

[0039] Preferably, the weight percentage of carbomer is 1-20% based on the total weight of the prescription; more preferably 1-15%, more preferably 1-10%, and even more preferably 1-6%.

[0040] In this invention, when the adhesive uses a combination of polyethylene oxide and carbomer, the weight percentage of polyethylene oxide to carbomer can be 10:1 to 1:5, 10:1 to 1:1, 8:1 to 2:1, 8:1 to 4:1, 6:1 to 4:1 or 4:1 to 2:1.

[0041] Disintegrants facilitate tablet disintegration or release. Available disintegrants include, but are not limited to, crospovidone, crospovidone sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, starch, modified starch, microcrystalline cellulose, sodium alginate, or methylcellulose. Modified starch includes carboxymethyl starch, pregelatinized starch, or hydroxypropyl starch.

[0042] In this invention, the disintegrant can be crospovidone, a water-insoluble disintegrant such as crospovidone, preferably a synthetic crospovidone N-vinyl-2-pyrrolidone homopolymer, which has high capillary activity and excellent hydration ability, does not form a gel layer, and plays a role in expanding the volume of solid formulations in flotation formulations. It can be used in conjunction with flotation materials and adhesives to improve their flotation performance and delay retention time. In this invention, the weight percentage of the disintegrant, based on the total weight of the formulation, is 0-20%; preferably 3-15%; more preferably 3-10%; and even more preferably 4-8%.

[0043] In this invention, a lubricant may also be added, which facilitates various process steps including component mixing, granulation, and tableting. Lubricants include, but are not limited to, talc, micronized silica gel, hydrogenated vegetable oil, mineral oil, sodium stearate fumarate, glyceryl behenate, sodium lauryl sulfate, polyethylene glycol, magnesium stearate, calcium stearate, zinc stearate, poloxamer, etc.; magnesium stearate is preferred. In this invention, the weight percentage of the lubricant, based on the total weight of the formulation, is 0–8%, preferably 0.1–5%, more preferably 0.1–3.5%, and even more preferably 0.25–2%.

[0044] In this invention, adhesives may also be added, including but not limited to povidone, copovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, starch paste, gelatin, polyethylene glycol, etc.; copovidone is preferred; in this invention, the weight percentage of the adhesive, based on the total weight of the formulation, is 0-15%, preferably 0.1-10%, more preferably 0.1-8%, further preferably 0.1-5%, even more preferably 0.1-3%, and most preferably 0.1-1.5%.

[0045] In this invention, a gas-generating agent may also be added, preferably an acid-sensitive gas-generating agent, including but not limited to sodium bicarbonate, calcium carbonate, sodium citrate, sodium carbonate, or tartaric acid, with sodium bicarbonate being preferred; in this invention, the weight percentage of the gas-generating agent based on the total weight of the formulation is 0-15%, preferably 0.1-10%, more preferably 0.1-8%, further preferably 0.1-5%, even more preferably 0.1-3.5%, and most preferably 0.1-2%.

[0046] In this invention, surfactants may also be added, including but not limited to poloxamer, sodium lauryl sulfate, polysorbate, or sodium dodecylbenzene sulfonate; poloxamer is preferred; in this invention, the weight percentage of surfactants based on the total weight of the formulation is 0-15%, preferably 0.1-10%, more preferably 0.1-8%, further preferably 0.1-5%, even more preferably 0.1-3%, and most preferably 0.1-1.5%.

[0047] In this invention, the inventors discovered that preparing a sustained-release drug composition into a bilayer tablet can achieve better buoyancy and sustained-release capabilities. In a preferred embodiment, the sustained-release drug composition includes a floating layer and a drug-containing layer, wherein the floating layer contains a buoyancy material and the drug-containing layer contains a sustained-release material.

[0048] Alternatively, depending on the specific preparation requirements, multilayer sheets can be prepared or coated.

[0049] In a preferred embodiment of the present invention, the floating layer comprises one or more of a flocculating material, an adhesive, a disintegrant, and a lubricant; preferably, the floating layer comprises a flocculating material and an adhesive; or, a flocculating material, an adhesive, a disintegrant, and a lubricant; or, a flocculating material, an adhesive, a disintegrant, and a lubricant. Alternatively, the flocculating material, an adhesive, a disintegrant, and a lubricant may also contain other pharmaceutically acceptable excipients.

[0050] Optionally, a gas-generating agent can also be added.

[0051] Based on the total weight of the floating layer (100%), the weight percentage of the floating material can be 20-70%, 25-65%, 30-60%, 35-55%, 40-60%, or 45-55%.

[0052] Based on the total weight of the floating layer (100%), the weight percentage of the adhesive is 20-70%, 20-60%, 25-65%, 30-60%, 30-55%, 30-50%, or 30-45%.

[0053] When the adhesive uses a combination of polyethylene oxide and carbomer, the weight percentage of polyethylene oxide is 20-50%, 24-45%, 27-45%, 28-40%, 29-40%, 30-40%, 30-38%, or 30-35% based on 100% of the total weight of the floating layer; the weight percentage of carbomer is 0-20%, 1-20%, 1-18%, 1-15%, 1-10%, 2-15%, or 3-15% based on 100% of the total weight of the floating layer.

[0054] Based on 100% of the total weight of the floating layer, the weight percentage of the disintegrant is 0-20%, 2-20%, 5-20%, 5-18%, or 5-15%.

[0055] Based on 100% of the total weight of the floating layer, the lubricant content is 0-5%, 0.1-3.5%, 0.25-2.5%, or 0.25-2%.

[0056] In a preferred embodiment of the present invention, the drug-containing layer includes one or more of a drug, a sustained-release material, a filler, and a lubricant; preferably, the drug-containing layer includes a drug and a sustained-release material; or, the drug-containing layer includes a drug, a sustained-release material, and a filler; or, the drug-containing layer includes a drug, a sustained-release material, a filler, and a lubricant.

[0057] Optional additions include adhesives, surfactants, or a combination of both.

[0058] Based on 100% of the total weight of the drug-containing layer, the drug content is 1-40%, 5-40%, 5-35%, 10-35%, 15-35%, or 20-35%.

[0059] Based on the total weight of the drug-containing layer (100%), the weight percentage of the sustained-release material is 1–50%, 1–40%, 5–35%, 2–45%, 5–40%, 5–30%, 5–25%, 5–20%, or 5–15%.

[0060] Based on the total weight of the drug-containing layer (100%), the weight percentage of the filler is 0–88%, 10–80%, 20–75%, 25–70%, 30–70%, 40–70%, 50–70%, or 55–65%.

[0061] When the filler is selected from a combination of lactose and microcrystalline cellulose, the weight percentage of lactose, based on 100% of the total weight of the drug-containing layer, is 10–60%, 15–55%, 20–55%, 20–50%, 25–50%, 30–50%, 35–50%, or 40–50%; and the weight percentage of microcrystalline cellulose, based on 100% of the total weight of the drug-containing layer, is 0–28%, 1–25%, 5–25%, 0–20%, 5–20%, or 10–20%.

[0062] Based on 100% of the total weight of the medicated layers, the lubricant content is 0-5%, 0.1-3.5%, 0.25-2.5%, or 0.25-2%.

[0063] In a preferred embodiment of the present invention, based on 100% of the total weight of the floating layer formulation, the weight percentages of each component are as follows: 20-70% floating material, 20-70% adhesive, 0-25% disintegrant, and 0-5% lubricant; more preferably, 25-65% floating material, 25-65% adhesive, 1-20% disintegrant, and 0.1-3.5% lubricant; even more preferably, 30-60% floating material, 30-60% adhesive, 1-20% disintegrant, and 0.1-3.5% lubricant. The preferred composition is 0.1-3.5% flotation agent; further preferably 40-60% flotation material, 30-55% adhesive, 2-20% disintegrant, and 0.25-2.5% lubricant; even more preferably 45-55% flotation material, 30-50% adhesive, 5-15% disintegrant, and 0.25-2.5% lubricant; most preferably 45-55% flotation material, 30-45% adhesive, 5-15% disintegrant, and 0.25-2.5% lubricant.

[0064] In a preferred embodiment of the present invention, based on 100% of the total weight of the drug-containing layer formulation, the weight percentages of each component are as follows: drug 1-40%, sustained-release material 1-60%, filler 0-80%, lubricant 0-5%; or, drug 1-40%, sustained-release material 1-50%, filler 0-80%, lubricant 0-5%; or, drug 5-35%, sustained-release material 1-40%, filler 25-70%, lubricant 0.1-3.5%; or, drug 15-35%, sustained-release material 5-35%, filler 30-70%, lubricant 0.1-3.5%; or, drug 20-35%, sustained-release material 5-25%, filler 40-70%, lubricant 0.1-3.5%; or, drug 20-35%, sustained-release material 5-15%, filler 50-70%, lubricant 0.5-2.5%.

[0065] In a preferred embodiment of the present invention, the sustained-release pharmaceutical composition comprises the following components: a drug, a buoyancy material, and a sustained-release material; or, a drug, a buoyancy material, a sustained-release material, and an adhesive; or, a drug, a buoyancy material, a sustained-release material, an adhesive, and a lubricant; or, a drug, a buoyancy material, a sustained-release material, an adhesive, a filler, and a lubricant; or, a drug, a buoyancy material, a sustained-release material, an adhesive, a disintegrant, and a lubricant; or, a drug, a buoyancy material, a sustained-release material, an adhesive, a filler, a disintegrant, and a lubricant; optionally, other pharmaceutical excipients, including surfactants, binders, flow aids, etc., are added.

[0066] In a preferred embodiment of the present invention, the sustained-release drug composition comprises the following components: the floating layer comprises a floating material and an adhesive, and the drug-containing layer comprises a drug and a sustained-release material; or, the floating layer comprises a floating material, an adhesive, and a filler, and the drug-containing layer comprises a drug and a sustained-release material; or, the floating layer comprises a floating material, an adhesive, and a lubricant, and the drug-containing layer comprises a drug and a sustained-release material; or, the floating layer comprises a floating material, an adhesive, and a filler, and the drug-containing layer comprises a drug, a sustained-release material, and a lubricant; or, the floating layer comprises a floating material, an adhesive, and a filler, and the drug-containing layer comprises a drug, a sustained-release material, and a lubricant; or, the floating layer comprises a floating material, an adhesive, and a filler, and the drug-containing layer comprises a drug, a sustained-release material, and a lubricant. Materials, adhesives, and lubricants; the drug-containing layer includes a drug, a sustained-release material, and a lubricant; or, the floating layer includes a floating material, an adhesive, and a filler, and the drug-containing layer includes a drug, a sustained-release material, and a disintegrant; or, the floating layer includes a floating material, an adhesive, and a lubricant; the drug-containing layer includes a drug, a sustained-release material, a filler, and a lubricant; or, the floating layer includes a floating material, an adhesive, a disintegrant, and a lubricant, and the drug-containing layer includes a drug, a sustained-release material, a filler, and a lubricant; optionally, pharmaceutically acceptable excipients are added to each layer.

[0067] In a preferred embodiment of the present invention, the sustained-release drug composition comprises the following components: the floating layer comprises a mixture of polyvinyl acetate and povidone, and carbomer; the drug-containing layer comprises lurasidone hydrochloride and hydroxypropyl methylcellulose; or, the floating layer comprises a mixture of polyvinyl acetate and povidone, carbomer, and magnesium stearate; the drug-containing layer comprises lurasidone hydrochloride and hydroxypropyl methylcellulose; or, the floating layer comprises a mixture of polyvinyl acetate and povidone, carbomer, and magnesium stearate; the drug-containing layer comprises lurasidone hydrochloride and hydroxypropyl methylcellulose. Hydroxypropyl methylcellulose and magnesium stearate; or, the floating layer comprises a mixture of polyvinyl acetate and povidone, carbomer, polyoxyethylene, and magnesium stearate; the drug-containing layer comprises lurasidone hydrochloride, hydroxypropyl methylcellulose, lactose, and magnesium stearate; or, the floating layer comprises a mixture of polyvinyl acetate and povidone, carbomer, polyoxyethylene, and magnesium stearate, and the drug-containing layer comprises lurasidone hydrochloride, hydroxypropyl methylcellulose, lactose, microcrystalline cellulose, and magnesium stearate; optionally, pharmaceutically acceptable excipients are added to each layer.

[0068] In a preferred embodiment of the present invention, the weight percentage of each component, based on the total weight of the composition, is as follows:

[0069]

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[0071]

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[0076]

[0077] In a preferred embodiment of the present invention, the weight percentage of each component in each layer, based on the total weight of each layer, is as follows:

[0078]

[0079] Alternatively, the weight percentage of each component is:

[0080]

[0081] Alternatively, the weight percentage of each component is:

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[0083] Alternatively, the weight percentage of each component is:

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[0085] Alternatively, the weight percentage of each component is:

[0086]

[0087] In a preferred embodiment of the present invention, the weight percentage of each component in each layer, based on the total weight of each layer, is as follows:

[0088]

[0089] Alternatively, the weight percentage of each component is:

[0090]

[0091] Alternatively, the weight percentage of each component is:

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[0093] Alternatively, the weight percentage of each component is:

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[0095]

[0096] Alternatively, the weight percentage of each component is:

[0097]

[0098] In a preferred embodiment of the present invention, the weight percentage of each component in each layer, based on the total weight of each layer, is as follows:

[0099]

[0100] Alternatively, the weight percentage of each component is:

[0101]

[0102]

[0103] Alternatively, the weight percentage of each component is:

[0104]

[0105] Alternatively, the weight percentage of each component is:

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[0107]

[0108] Alternatively, the weight percentage of each component is:

[0109]

[0110] Alternatively, the weight percentage of each component is:

[0111]

[0112] The present invention also provides a method for preparing a sustained-release formulation composition, comprising: a floating layer using a powder direct pressing process and a drug-containing layer using a fluidized bed granulation process.

[0113] In this invention, the floating layer material is prepared by direct mixing, and the drug-containing layer material is prepared by fluidized bed granulation. During tableting, the floating layer is first added for pre-compression, and then the drug-containing layer is added and compressed into tablets. Further processing, such as coating and polishing, can be performed to improve the appearance of the tablet surface and increase the strength of the floating tablets.

[0114] In a preferred embodiment of the present invention, the following steps are included:

[0115] Preparation of the floating layer mixture: Mix the floating material, adhesive, disintegrant, and lubricant thoroughly.

[0116] Preparation of drug-containing particles: The active ingredient, sustained-release material, filler, and lubricant are granulated in a fluidized bed.

[0117] The prepared intermediate was pressed into a bilayer sheet;

[0118] Preferably, it includes the following steps:

[0119] Preparation of the floating layer intermediate: A mixture of polyvinyl acetate and polyvinyl chloride, polyethylene oxide, carbomer, and crosslinked polyvinyl chloride was thoroughly mixed, and then magnesium stearate was added and mixed thoroughly.

[0120] Preparation of drug-containing intermediates: The drug, lactose, microcrystalline cellulose, and hydroxypropyl methylcellulose were wet-granulated in a fluidized bed, and then magnesium stearate was added and mixed thoroughly.

[0121] The intermediate obtained in the above steps is pressed into a double-layer sheet.

[0122] More preferably, when the drug is lurasidone hydrochloride, the following steps are included:

[0123] Preparation of the floating layer intermediate: A mixture of polyvinyl acetate and polyvinyl chloride, polyethylene oxide, carbomer, and crosslinked polyvinyl chloride was thoroughly mixed, and then magnesium stearate was added and mixed thoroughly.

[0124] Preparation of drug-containing intermediates: Lurasidone hydrochloride was wet-granulated with lactose, microcrystalline cellulose, and hydroxypropyl methylcellulose in a fluidized bed, and then magnesium stearate was added and mixed thoroughly.

[0125] The intermediate obtained above is pressed into a bilayer sheet.

[0126] To prepare gastric floating tablets, the processes for the floating layer and drug-containing layer were studied separately. To improve the floating performance and drug release properties of the gastric floating tablets, the floating layer and drug-containing layer materials were prepared separately and then compressed into bilayer tablets. For example, the floating layer intermediate was first pre-compressed, and then the drug-containing layer intermediate was added and compressed into tablets.

[0127] In this invention, the particle size of the drug is d90<300μm, d90<200μm, d90<160μm, d90<120μm, d90<80μm, d90<50μm, d90<20μm, d90<10μm, d90<5μm, d90<1μm, or a combination of several particle size ranges.

[0128] When the drug is lurasidone hydrochloride, the particle size is d90 < 10 μm, less than d90 < 5 μm, or d90 < 1 μm. Reducing the particle size can improve its solubility and drug release rate to a certain extent.

[0129] In this invention, it is preferred that the intermediate material is sieved during the preparation process, preferably through a 10-60 mesh sieve, a 10-45 mesh sieve, a 10-30 mesh sieve, or a 20-24 mesh sieve.

[0130] When the floating tablet is taken into the patient's body, it first comes into contact with the gastric juice in the patient's stomach and begins to swell or expand, thus playing a floating role and ensuring that the floating tablet stays in the stomach. The drug-containing layer slowly releases the drug, thereby reducing the influence of food, prolonging the retention time in the stomach and the drug release time, avoiding the peak and trough phenomenon caused by the rapid release of ordinary preparations, improving bioavailability, and improving patient compliance.

[0131] When lurasidone hydrochloride is selected as the drug, the sustained-release pharmaceutical composition prepared by the present invention can also be used to prepare drugs for treating mental illnesses, preferably schizophrenia.

[0132] The sustained-release drug composition prepared by this invention has the following advantages:

[0133] 1. It solves the problem that drugs that are poorly soluble in alkaline pH values ​​have a short residence time in the stomach, low absorption, and low bioavailability;

[0134] 2. Short floatation time, floats quickly within 10 seconds, strong float holding power, can float continuously for more than 8 hours, effectively reducing the frequency of medication for patients;

[0135] 3. Because the prepared sustained-release drug composition has strong buoyancy and adhesion, it can achieve good therapeutic effects under different physiological conditions (different gastric motility).

[0136] 4. The auxiliary materials used are readily available, the process is controllable and reproducible, and it is easy to scale up industrial production.

[0137] On the other hand, the lurasidone hydrochloride sustained-release drug composition prepared by the present invention has the advantages of good stability and stable quality, and has a significant sustained-release effect compared with commercially available ordinary tablets. Attached Figure Description

[0138] Figure 1 Figure showing the in vitro release of the lurasidone hydrochloride formulation composition. Detailed Implementation

[0139] The present invention will be further described in detail below with reference to the embodiments, but is not limited to the embodiments described below.

[0140] Example 1

[0141] prescription

[0142]

[0143] The preparation steps are as follows:

[0144] Floating layer: Thoroughly mix polyvinyl acetate-polyvinyl ketone mixture and polycarbomer;

[0145] Drug-containing layer: Lurasidone hydrochloride and hydroxypropyl methylcellulose were granulated in a fluidized bed, and purified water was used as a wetting agent to prepare drug-containing particles;

[0146] The two parts of material are pressed into a double-layer sheet.

[0147] Example 2

[0148] prescription

[0149]

[0150] The preparation steps are as follows:

[0151] Floating layer:

[0152] 1) Thoroughly mix the polyvinyl acetate-polyvinyl ketone mixture and polycarbomer;

[0153] 2) Add magnesium stearate to the above materials and mix evenly to form a floating layer.

[0154] Drug-containing layer:

[0155] 1) Lurasidone hydrochloride and hydroxypropyl methylcellulose were granulated in a fluidized bed, and purified water was used as a wetting agent to prepare drug-containing particles;

[0156] 2) Add magnesium stearate to the above granules and mix evenly to form a drug-containing layer.

[0157] The two parts of material are pressed into a double-layer sheet.

[0158] Example 3

[0159] prescription:

[0160]

[0161]

[0162] The preparation steps are as follows:

[0163] Floating layer:

[0164] 1) Thoroughly mix the polyvinyl acetate-polyvinyl ketone mixture, carbomer, and crosslinked polyvinyl ketone;

[0165] 2) Add magnesium stearate to the above materials and mix evenly to form a floating layer.

[0166] Drug-containing layer:

[0167] 3) Lurasidone hydrochloride and lactose hydroxypropyl methylcellulose were granulated in a fluidized bed, with purified water as a wetting agent, to prepare drug-containing particles;

[0168] 4) Add magnesium stearate to the above granules and mix evenly to form a drug-containing layer.

[0169] The two parts of material are pressed into a double-layer sheet.

[0170] Example 4

[0171] prescription:

[0172]

[0173] The preparation steps are as follows:

[0174] Floating layer:

[0175] 1) Thoroughly mix the polyvinyl acetate-polyvinyl ketone mixture, carbomer, and crosslinked polyvinyl ketone;

[0176] 2) Add magnesium stearate to the above materials and mix evenly to form a floating layer.

[0177] Drug-containing layer:

[0178] 5) Lurasidone hydrochloride was granulated with lactose, lactose and hydroxypropyl methylcellulose in a fluidized bed, and purified water was used as a wetting agent to prepare drug-containing particles;

[0179] 6) Add magnesium stearate to the above granules and mix evenly to form a drug-containing layer.

[0180] The two parts of material are pressed into a double-layer sheet.

[0181] Example 5

[0182] prescription:

[0183]

[0184] The preparation steps are as follows:

[0185] Floating layer:

[0186] 1) Thoroughly mix the polyvinyl acetate-polyvinyl ketone mixture, polyethylene oxide, carbomer, and crosslinked polyvinyl ketone;

[0187] 2) Add magnesium stearate to the above materials and mix evenly to form a floating layer.

[0188] Drug-containing layer:

[0189] 7) Lurasidone hydrochloride was granulated with lactose, lactose and hydroxypropyl methylcellulose in a fluidized bed, and purified water was used as a wetting agent to prepare drug-containing particles;

[0190] 8) Add magnesium stearate to the above granules and mix evenly to form a drug-containing layer.

[0191] The two parts of material are pressed into a double-layer sheet.

[0192] Example 6

[0193] prescription

[0194]

[0195] The preparation steps are as follows:

[0196] Floating layer:

[0197] 1) Thoroughly mix the polyvinyl acetate-polyvinyl ketone mixture, polyethylene oxide, carbomer, and crosslinked polyvinyl ketone;

[0198] 2) Add magnesium stearate to the above materials and mix evenly to form a floating layer.

[0199] Drug-containing layer:

[0200] 9) Lurasidone hydrochloride was granulated with lactose, microcrystalline cellulose, and hydroxypropyl methylcellulose in a fluidized bed, with purified water as a wetting agent, to prepare drug-containing particles;

[0201] 10) Add magnesium stearate to the above granules and mix evenly to form a drug-containing layer.

[0202] The two parts of material are pressed into a double-layer sheet.

[0203] Example 7

[0204] prescription:

[0205]

[0206]

[0207] The preparation steps were carried out in a manner similar to that described in Example 6.

[0208] Example 8

[0209] prescription:

[0210]

[0211] The preparation steps were carried out in a manner similar to that described in Example 6.

[0212] Example 9

[0213] prescription:

[0214]

[0215]

[0216] The preparation steps were carried out in a manner similar to that described in Example 6.

[0217] Example 10

[0218] prescription:

[0219]

[0220] The preparation steps were carried out in a manner similar to that described in Example 6.

[0221] Example 11

[0222] prescription:

[0223]

[0224]

[0225] The preparation steps were carried out in a manner similar to that described in Example 6.

[0226] Example 12

[0227] prescription:

[0228]

[0229] The preparation steps were carried out in a manner similar to that described in Example 6.

[0230] Example 13

[0231] prescription:

[0232]

[0233]

[0234] The preparation steps were carried out in a manner similar to that described in Example 6.

[0235] Example 14

[0236] prescription:

[0237]

[0238] The preparation steps were carried out in a manner similar to that described in Example 6.

[0239] Example 15

[0240] prescription:

[0241]

[0242]

[0243] The preparation steps were carried out in a manner similar to that described in Example 6.

[0244] Example 16

[0245] prescription:

[0246]

[0247] The preparation steps were carried out in a manner similar to that described in Example 6.

[0248] Example 17

[0249] prescription:

[0250]

[0251]

[0252] The preparation steps were carried out in a manner similar to that described in Example 6.

[0253] Comparative Example 1

[0254] prescription:

[0255]

[0256] The preparation steps are as follows: mix the above excipients and compress them directly into tablets.

[0257] Comparative Example 2

[0258] Prescription: Prescription:

[0259]

[0260]

[0261] The preparation steps are as follows: mix the above excipients and compress them directly into tablets.

[0262] Experimental Example 1

[0263] The study of physical properties:

[0264] Material compressibility coefficient

[0265] The bulk density and tap density of the floating layer and the drug-containing layer were measured separately, and the compressibility coefficient was calculated to evaluate the material flowability.

[0266] Compressibility

[0267] Tablets were compressed at the maximum hardness at which they could float, the hardness was recorded, and the tablet thickness was measured.

[0268] Floating performance

[0269] The experiment was conducted according to Method II of Dissolution and Release Determination, Part IV, General Chapter 0931, of the 2015 edition of the Chinese Pharmacopoeia. 900 mL of degassed pH 1.2 hydrochloric acid medium was used at a temperature of 37.0℃ ± 0.5℃ and a rotation speed of 50 r / min. The initiation time and floating time of different formulations of the floating tablets were recorded. The results are shown in the table below:

[0270]

[0271] In the embodiments of the present invention, the intermediate particles have good flowability, which meets the requirements of the production and preparation process. The finished tablets have suitable hardness, can float quickly, have a long floating time, and have excellent floating performance.

[0272] Experimental Example 2

[0273] Release rate study:

[0274] The experiment was conducted according to the second method of Dissolution and Release Determination in General Chapter 0931 of Part IV of the 2015 edition of the Chinese Pharmacopoeia. 900 mL of degassed pH 1.2 hydrochloric acid medium was used, the medium temperature was 37.0℃ ± 0.5℃, the rotation speed was 50 r / min, and sampling points were 1, 2, 4, 6, 8, and 12 hours.

[0275] Determination method: High performance liquid chromatography (HPLC) was performed using an Xselect CSH C18 column. The mobile phase was phosphate buffer (pH 4.0)-acetonitrile = 40:60, and the flow rate was 1.0 mL / min. The detection wavelength was 230 nm. The release rate results are as follows:

[0276]

[0277] The bilayer sustained-release drug composition of the present invention can sustain release for 12 hours, which is suitable for release time and has a good sustained-release effect compared with commercially available products and single-layer tablets.

[0278] Experimental Example 3

[0279] Stability study:

[0280] The samples prepared in Examples 1-17 were compared with commercially available products. (Specification 40mg) After being packaged in aluminum-plastic packaging, the stability was tested under accelerated conditions of 40℃ / RH75%.

[0281] Determination method: High performance liquid chromatography (HPLC) was performed using an XBridge C18 column, with mobile phase A being phosphate buffer (pH 7.0)-acetonitrile = 80:20 and mobile phase B being acetonitrile, at a flow rate of 1.0 mL / min; the detection wavelength was 210 nm. The results are shown in the table below:

[0282]

[0283] The embodiments of the present invention showed no significant changes in related substances and good stability after being stored under accelerated conditions for 6 months.

Claims

1. A sustained-release pharmaceutical composition of lurasidone hydrochloride, characterized in that, It is a double-layer tablet, comprising a floating layer and a drug-containing layer, wherein the floating layer comprises a floating material, an adhesive, a disintegrant, and a lubricant, and the drug-containing layer comprises lurasidone hydrochloride, a sustained-release material, a filler, and a lubricant; The floating material is a mixture of polyvinyl acetate and povidone in a ratio of 80:19, accounting for 25-35% of the total weight of the prescription; The adhesive is a combination of polyethylene oxide and carbomer, with polyethylene oxide accounting for 15-25% of the total weight of the formulation and carbomer accounting for 1-6% of the total weight of the formulation. The disintegrant is crospovidone, accounting for 4-8% of the total weight of the formulation. The weight of lurasidone hydrochloride is 5-15% of the total weight of the prescription; The sustained-release material is hydroxypropyl methylcellulose, accounting for 1-6% of the total weight of the formulation. The filler is a combination of lactose and microcrystalline cellulose, with lactose accounting for 12-20% of the total weight of the prescription and microcrystalline cellulose accounting for 3-8% of the total weight of the prescription. The lubricant is magnesium stearate, which accounts for 0.25-2% of the total weight of the prescription.

2. The lurasidone hydrochloride sustained-release pharmaceutical composition according to claim 1, characterized in that, Based on the total weight of the floating layer formulation (100%), the weight percentages of each component are as follows: floating material 45-55%, adhesive 30-45%, disintegrant 5-15%, and lubricant 0.25-2.5%.

3. The lurasidone hydrochloride sustained-release pharmaceutical composition according to claim 1, characterized in that, Based on 100% of the total weight of the drug-containing formulation, the weight percentage of each component is as follows: lurasidone hydrochloride 20-35%, sustained-release material 5-15%, filler 50-70%, and lubricant 0.5-2.5%.

4. The lurasidone hydrochloride sustained-release pharmaceutical composition according to claim 1, characterized in that, Each unit dose of the sustained-release drug composition contains 20 mg, 40 mg, 60 mg, 80 mg, or 120 mg of lurasidone hydrochloride.

5. A method for preparing the lurasidone hydrochloride sustained-release pharmaceutical composition according to any one of claims 1-4, characterized in that, The floating layer is produced using a direct powder compression process, while the drug-containing layer is produced using a fluidized bed granulation process.

6. The method according to claim 5, characterized in that, Includes the following steps: Preparation of the floating layer intermediate: A mixture of polyvinyl acetate and polyvinyl chloride, polyethylene oxide, carbomer, and crosslinked polyvinyl chloride was thoroughly mixed, and then magnesium stearate was added and mixed thoroughly. Preparation of drug-containing intermediates: Lurasidone hydrochloride was wet-granulated with lactose, microcrystalline cellulose, and hydroxypropyl methylcellulose in a fluidized bed, and then magnesium stearate was added and mixed thoroughly. The intermediate obtained in the above steps is pressed into a double-layer sheet.

7. The method according to claim 5 or 6, characterized in that, The particle size of the drug is d 90 <5μm.

8. The method according to claim 5 or 6, characterized in that, The particle size of the drug is d 90 <1μm.

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