A gastric retentive pregabalin sustained-release composition and preparation method thereof

Abstract

The present invention discloses a gastric retentive pregabalin sustained-release composition and a preparation method thereof. The present invention provides a gastric retentive pregabalin sustained-release composition comprising the following components: pregabalin, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, a matrix-forming agent, a swellable polymer, and a gelling agent. This sustained-release composition can achieve gastric retention under conditions of normal gastric acid secretion, gastric acid deficiency, or hypoacidity, providing stable drug release and improved drug stability.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and particularly relates to a gastric retentive pregabalin sustained-release composition and a preparation method thereof. Background Art

[0002] Pregabalin is a structural analog of γ-aminobutyric acid that has been approved for the treatment of neuropathic pain, including painful diabetic peripheral neuropathy, postherpetic neuralgia, and generalized anxiety disorder. It is also used as an adjunctive treatment for partial and refractory epileptic seizures. Pregabalin was originally marketed as an immediate-release (IR) tablet with an elimination half-life of only 4.0-6.3 hours, requiring two to three doses per day. However, neuropathic pain is a chronic disease, and multiple doses may affect patient compliance with treatment. To address the issue of frequent dosing, the development of a sustained-release (SR) tablet that can be administered once daily is expected to bring convenience to patients by reducing the frequency of dosing.

[0003] Clinical studies have shown that pregabalin is heterogeneously absorbed in the gastrointestinal tract. It is absorbed in the small intestine and ascending colon in humans, but is rarely absorbed in the intestinal segments beyond the hepatic flexure of the colon. This suggests that pregabalin's average absorption window is approximately 6 hours or less. If pregabalin is formulated into a conventional sustained-release dosage form, a formulation with a release time exceeding 6 hours will pass through the hepatic flexure of the colon, and the released drug will not be effectively absorbed. Therefore, there is a need to develop a sustained-release formulation of pregabalin that can retain the drug in the upper gastrointestinal tract for a longer period of time. Furthermore, another major issue with pregabalin formulations is that pregabalin is prone to cyclization during storage to form lactam impurities. Therefore, developing a formulation that reduces pregabalin's tendency to form lactam impurities would be beneficial.

[0004]

[0005] Gastric retentive drug delivery systems (GRDDS) are an effective means of prolonging drug retention in the stomach and achieving slow drug release. The main mechanisms of action of GRDDS include flotation, sinking, swelling, effervescence, and mucosal adhesion, with a combination of flotation and swelling being the most effective. These systems typically contain the drug and one or more swellable polymers that swell upon absorption of gastric fluid, allowing the tablet to float on the gastric contents. However, the effectiveness of flotation systems depends on the duration of high gastric fluid levels; the flotation time decreases as gastric fluid levels decrease and reach the pylorus. Swelling systems may be ineffective in patients with achlorhydria, as swelling is incomplete or slow in the absence of gastric fluid, potentially leading to premature gastric emptying.

[0006] Gastric acid secretion is influenced by physiological or pathological factors such as race, age, disease, diet, and concomitant medications. The average gastric pH in fasting healthy subjects is 1.1±0.15, while the average gastric pH in the fed state is 3.6±0.4, returning to baseline levels within approximately 2 to 4 hours. Achlorhydria is a common clinical condition affecting a wide range of people and has a high incidence. In patients with achlorhydria, the average gastric pH is much higher than in healthy individuals. Patients treated with antacids and acid suppressants experience decreased gastric acidity and increased pH. For example, omeprazole (PPI) has been reported to raise gastric pH to approximately 6.0. Patients with HIV / AIDS have decreased gastric acid secretion, resulting in an average fasting gastric pH of approximately 5.9. Gastric acidity is also age-related. Studies have shown that the incidence of elevated gastric pH is higher in elderly subjects compared to younger age groups, with approximately 10% of elderly subjects experiencing an elevated gastric pH greater than 5.0.

[0007] However, the gastric retention preparations of pregabalin reported so far do not take into account the adverse effects of higher gastric pH on drug release in patients with gastric achlorhydria or inadequate secretion. In order to achieve longer retention of pregabalin in the stomach, many existing technologies use methacrylate copolymers. As a sustained-release matrix. The physicochemical properties of Eudragit (also known as Eudragit) depend on its chemical structure, and it is available in a variety of physical forms (aqueous dispersion, organic solution granules and powder). According to its properties, Eudragit can be divided into two categories: 1) pH-dependent polymers, whose solubility depends on the pH value and can be further divided into gastric-soluble polymers and enteric-soluble polymers. For gastric-soluble polymers, they are soluble below pH 5.5, such as E series (polymerized from butyl methacrylate, (2-dimethylaminoethyl) methacrylate, and methyl methacrylate); for enteric polymers, they are soluble when the pH exceeds 5.5, such as L series (polymerized from methacrylic acid and methyl methacrylate), S series (polymerized from methacrylic acid and methyl methacrylate), FS series (polymerized from methyl acrylate, methyl methacrylate, and methacrylic acid); 2) pH-independent polymers, which are neutral copolymers that are insoluble in aqueous solution at any pH value, but can penetrate and swell in digestive fluids; one of them is RS series, RL series are polymerized from ethyl acrylate, methyl methacrylate and trimethylaminoethyl methacrylate chloride, and have similar physical and chemical properties. The other type is ethyl acrylate-methyl methacrylate polymer, mainly NM series, NE series, both are made of ethyl acrylate and methyl methacrylate in a 2:1 ratio. Only the emulsifiers they contain are slightly different, but their main physical and chemical properties are basically the same.

[0008] Prior art CN109044981A discloses a pregabalin gastric floating sustained-release tablet, which uses a composition of hypromellose and methacrylate copolymer as a skeleton material. After contacting human gastric juice, this preparation floats on the upper part of the gastric juice and swells rapidly, thereby prolonging the retention time of the preparation in the stomach. The methacrylate copolymer used in this patent is If this dosage form is administered to patients with achlorhydria or hyposecretion, it is difficult to achieve the purpose of gastric retention.

[0009] Prior art US20210000775A1 discloses a pregabalin gastric retention tablet, which found that when using hypromellose as a sustained-release matrix, the drug release was slow when fasting and fast when eating. In order to reduce the food effect and prolong the gastric retention time, it uses hypromellose and PO combination as a sustained-release matrix to accelerate drug release during fasting and relatively reduce the food effect. However, this strategy is ineffective in patients with achlorhydria or hyposecretion.

[0010] In order to avoid the drug release being affected by gastric pH, CN114028355A discloses a method using an insoluble methacrylate copolymer. When used in combination with a polyvinyl acetate-povidone mixture as a matrix material, the formulation exhibited relatively consistent dissolution rates in media at pH 4.5 and pH 6.8. There are stability issues when combined with pregabalin due to obvious raw material and excipient compatibility.

[0011] Since the physicochemical properties of excipients play an important role in gastric retentive drug delivery systems, selecting a suitable swellable matrix polymer is very important for the development of gastric retentive sustained-release dosage forms. Summary of the Invention

[0012] The technical problem to be solved by the present invention is that existing sustained-release preparations have poor sustained-release effects in patients with gastric achloridia or hyposecretion, and some sustained-release preparations have poor drug stability and produce lactam impurities. To this end, the present invention provides a gastric retentive pregabalin sustained-release composition and a preparation method thereof. The composition has the following advantages: (1) the pregabalin sustained-release composition of the present invention can achieve gastric retention under conditions of normal gastric acid secretion, gastric achloridia, or hyposecretion, thereby achieving stable drug release; and (2) high stability and less prone to the formation of lactam impurities.

[0013] The present invention provides a gastric retentive sustained-release pharmaceutical composition comprising the following components:

[0014] 15 wt% to 40 wt% active ingredient; the active ingredient is pregabalin, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof;

[0015] 10 wt% to 20 wt% of a matrix forming agent; the matrix forming agent is a copolymer formed by polymerization of ethyl acrylate and methyl methacrylate;

[0016] 30 wt% to 60 wt% of a swellable polymer;

[0017] 3wt% to 10wt% gelling agent;

[0018] The wt% refers to the mass proportion of the component in the gastric retention sustained-release pharmaceutical composition.

[0019] In a certain embodiment, some technical features of the gastric retentive sustained-release pharmaceutical composition are described below, and the remaining technical features are as described in any other embodiment (hereinafter referred to as "in a certain embodiment"): the active ingredient is preferably pregabalin.

[0020] In a certain embodiment, the gastric retentive sustained-release pharmaceutical composition preferably contains 20 wt% to 35 wt% of the active ingredient, more preferably 25 wt% to 30 wt% of the active ingredient, and even more preferably 29.34 wt% of the active ingredient.

[0021] The “matrix forming agent” refers to a pharmaceutically acceptable material suitable for preparing oral dosage forms, which imparts structural integrity to the pharmaceutical composition and helps control or prolong the release rate of the drug and has other functions.

[0022] In one embodiment, the matrix forming agent is preferably a copolymer of ethyl acrylate and methyl methacrylate in a molar ratio of 2:1; the matrix forming agent is preferably of the following type: The copolymer and / or type is The copolymer of 30D copolymer, model 30D copolymer and model One or more of the copolymers of 40D, further preferably the model is 30D copolymer.

[0023] In one embodiment, the gastric retentive sustained-release pharmaceutical composition preferably contains 10 wt% to 15 wt% of the matrix-forming agent, more preferably 11 wt% to 14 wt% of the matrix-forming agent, and further preferably 11.5 wt%, 12.5 wt%, 13.5 wt% or 14 wt% of the matrix-forming agent.

[0024] The "swellable polymer" refers to a pharmaceutically acceptable material that rapidly absorbs water and expands in volume upon contact with an aqueous medium, thereby increasing the volume of the entire pharmaceutical composition and achieving gastric retention. The swellable polymer can also impart buoyancy to the pharmaceutical composition by entrapped air. The "swellable polymer" can be either a water-soluble polymer or a water-insoluble polymer.

[0025] In a certain embodiment, the swellable polymer is preferably one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, gum, chitosan, polyoxyethylene (also known as polyethylene oxide), xanthan gum, guar gum, sodium alginate, carbomer, crospovidone and cross-linked sodium carboxymethyl cellulose, more preferably crospovidone and / or polyoxyethylene, further preferably crospovidone and polyoxyethylene.

[0026] In one embodiment, the molecular weight of the polyoxyethylene is preferably 1×10 5 to 1×10 7 Polyoxyethylene, more preferably with a molecular weight of 1×10 6 to 1×10 7 of polyoxyethylene.

[0027] In a certain embodiment, the gastric retentive sustained-release pharmaceutical composition preferably contains 35 wt% to 55 wt% of the swellable polymer, more preferably 40 wt% to 50 wt% of the swellable polymer, and further preferably 43.5 wt% to 46.5 wt% of the swellable polymer.

[0028] In a certain embodiment, when the swellable polymers are crospovidone and polyoxyethylene, the gastric retentive sustained-release pharmaceutical composition preferably comprises 10wt% to 40wt% of the crospovidone and 5wt% to 35wt% of the polyoxyethylene, more preferably comprises 15wt% to 35wt% of the crospovidone and 10wt% to 30wt% of the polyoxyethylene, further preferably comprises 20wt% to 30wt% of the crospovidone and 15wt% to 25wt% of the polyoxyethylene, and still further preferably comprises 25wt% to 27wt% of the crospovidone and 18.5wt% to 19.5wt% of the polyoxyethylene, for example, 27wt% of the crospovidone and 19.5wt% of the polyoxyethylene or 25wt% of the crospovidone and 18.5wt% of the polyoxyethylene.

[0029] The "gelling agent," also known as a hydrocolloid, includes synthetic and natural polymers that generally have low water solubility (e.g., slightly soluble to poorly soluble). When exposed to water, the gelling agent forms a viscous mixture that can retard the diffusion of the drug in the composition, thereby extending the time it takes to release the drug from the dosage form.

[0030] In a certain embodiment, the gelling agent is preferably one or more of carbomer, xanthan gum, inulin, guar gum, chitosan, locust bean gum, carrageenan and cellulose derivatives, more preferably carbomer.

[0031] In a certain embodiment, the cellulose derivative is preferably one or more of methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate, carboxymethyl cellulose, carboxymethyl ethyl cellulose, hydroxyethyl methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate succinate and cellulose acetate trimellitate.

[0032] In a certain embodiment, the gastric retentive sustained-release pharmaceutical composition preferably contains 4wt% to 7wt% of the gel, more preferably contains 5wt% to 6wt% of the gel, and further preferably contains 5.5wt% to 5.9wt% of the gel, for example, contains 5.5wt% or 5.9wt% of the gel.

[0033] In a certain embodiment, the gastric retentive sustained-release pharmaceutical composition further comprises one or more of a pore-forming agent, a lubricant, a glidant, a filler, a disintegrant, a plasticizer, and a surfactant.

[0034] In a certain embodiment, the gastric retention sustained-release pharmaceutical composition comprises the following components: the active ingredient, the matrix forming agent, the swellable polymer, the gelling agent, the pore-forming agent, the lubricant and the glidant.

[0035] In a certain embodiment, the gastric retention sustained-release pharmaceutical composition is composed of the following components: the active ingredient, the matrix forming agent, the swellable polymer, the gelling agent, the pore-forming agent, the lubricant and the glidant.

[0036] In a certain embodiment, the porogen is preferably one or more of polyethylene glycol, povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvinyl alcohol, more preferably povidone.

[0037] In a certain embodiment, the gastric retentive sustained-release pharmaceutical composition preferably contains 2 wt% to 20 wt% of the pore-forming agent, more preferably contains 3 wt% to 15 wt% of the pore-forming agent, further preferably contains 5 wt% to 10 wt% of the pore-forming agent, and further preferably contains 6 wt%, 7 wt% or 8 wt% of the pore-forming agent.

[0038] In a certain embodiment, the lubricant is preferably one or more of talc, stearic acid, magnesium stearate, zinc stearate, calcium stearate, sodium stearyl fumarate and hydrogenated castor oil, more preferably magnesium stearate.

[0039] In a certain embodiment, the gastric retentive sustained-release pharmaceutical composition preferably contains 0wt% to 10wt% of the lubricant, more preferably contains 0.1wt% to 5wt% of the lubricant, further preferably contains 0.2wt% to 2wt% of the lubricant, and further preferably contains 0.5wt% of the lubricant.

[0040] In a certain embodiment, the glidant is preferably one or more of colloidal silicon dioxide, talc and starch, more preferably colloidal silicon dioxide.

[0041] In a certain embodiment, the gastric retentive sustained-release pharmaceutical composition preferably contains 0wt% to 5wt% of the glidant, more preferably contains 0.05wt% to 3wt% of the glidant, further preferably contains 0.1wt% to 2wt% of the glidant, and further preferably contains 0.26wt% of the glidant.

[0042] In a certain embodiment, the filler is preferably one or more of lactose, sucrose, mannitol, xylitol, sorbitol, microcrystalline cellulose, starch, pregelatinized starch, calcium phosphate dihydrate and anhydrous calcium hydrogen phosphate.

[0043] In a certain embodiment, the gastric retentive sustained-release pharmaceutical composition preferably comprises 0 wt% to 15 wt% of the filler.

[0044] In a certain embodiment, the disintegrant is preferably one or more of sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, cross-linked polyvinyl pyrrolidone, microcrystalline cellulose, pregelatinized starch and gum.

[0045] In a certain embodiment, the gastric retentive sustained-release pharmaceutical composition preferably comprises 0 wt% to 10 wt% of the disintegrant.

[0046] In a certain embodiment, the plasticizer is preferably one or more of triethyl citrate, tributyl citrate, triacetin, phthalate and terephthalate, more preferably triethyl citrate.

[0047] In a certain embodiment, the gastric retentive sustained-release pharmaceutical composition preferably contains 0 wt% to 5 wt% of the plasticizer.

[0048] In a certain embodiment, the surfactant is preferably one or more of polysorbate, fatty acid glyceride (such as fatty acid monoglyceride, fatty acid diglyceride), sucrose fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene fatty alcohol ether, poloxamer, sodium lauryl sulfate and docusate sodium, more preferably sodium lauryl sulfate.

[0049] In a certain embodiment, the gastric retentive sustained-release pharmaceutical composition preferably contains 0 wt% to 5 wt% of the surfactant.

[0050] In a certain embodiment, the gastric retention sustained-release pharmaceutical composition comprises: 29.34wt% pregabalin, 25wt% to 27wt% crospovidone, 11.5wt% to 14wt% NM 30D, 6wt% to 8wt% povidone, 0.26wt% colloidal silicon dioxide, 18.5wt% to 19.5wt% polyethylene oxide, 5.5wt% to 5.9wt% carbomer and 0.5wt% magnesium stearate.

[0051] In a certain embodiment, the gastric retention sustained-release pharmaceutical composition comprises: 29.34 wt% pregabalin, 25 wt% crospovidone, 12.5 wt% NM 30D, 8 wt% povidone, 0.26 wt% colloidal silicon dioxide, 18.5 wt% polyethylene oxide, 5.9 wt% carbomer and 0.5 wt% magnesium stearate.

[0052] In a certain embodiment, the gastric retention sustained-release pharmaceutical composition comprises: 29.34 wt% pregabalin, 27 wt% crospovidone, 11.5 wt% NM 30D, 6 wt% povidone, 0.26 wt% colloidal silicon dioxide, 19.5 wt% polyethylene oxide, 5.9 wt% carbomer and 0.5 wt% magnesium stearate.

[0053] In a certain embodiment, the gastric retention sustained-release pharmaceutical composition comprises: 29.34 wt% pregabalin, 25 wt% crospovidone, 14 wt% NM 30D, 7 wt% povidone, 0.26 wt% colloidal silicon dioxide, 18.5 wt% polyethylene oxide, 5.5 wt% carbomer and 0.5 wt% magnesium stearate.

[0054] In a certain embodiment, the gastric retention sustained-release pharmaceutical composition comprises: 29.34 wt% pregabalin, 25 wt% crospovidone, 13.5 wt% NM 30D, 7 wt% povidone, 0.26 wt% colloidal silicon dioxide, 18.5 wt% polyethylene oxide, 5.9 wt% carbomer and 0.5 wt% magnesium stearate.

[0055] In a certain embodiment, the dosage form of the gastric retentive sustained-release pharmaceutical composition is preferably tablets, capsules, micropills, granules, powders or microtablets, more preferably tablets.

[0056] Described gastric retention type sustained-release pharmaceutical composition can be prepared by methods known in the art, for example, active ingredient and matrix forming agent, swellable polymer, gel and other pharmaceutically acceptable excipient can be directly mixed and compressed, or, in order to improve the homogeneity of product, can be merged and mixed components in stages. For example, active ingredient and one or more components in matrix forming agent, swellable polymer, gel and other pharmaceutically acceptable excipient are granulated by fluidized bed or extrusion granulation method, then mixed with all the other components. Or, active ingredient can first be mixed with one or more components in matrix forming agent, swellable polymer, gel and other pharmaceutically acceptable excipient, then mixed with other components in one or more mixing operations. If necessary, before mixing, the particle size of one or more components can be controlled by sieving or pulverizing.

[0057] In one embodiment, the gastric retentive sustained-release pharmaceutical composition can rapidly swell upon contact with water, and maintains good shape and rigidity after contact with water, thereby exhibiting more excellent gastric retentiveness.

[0058] In one embodiment, the gastric retentive sustained-release pharmaceutical composition can float within 15 minutes after contact with water, and the resulting floating state can be maintained for at least 12 hours.

[0059] In one embodiment, the release rate (cumulative dissolution rate) of the active ingredient (e.g., pregabalin) in the gastric retentive sustained-release pharmaceutical composition is less than 25% within 1 hour, 40% to 70% within 4 to 8 hours, and greater than 85% within 16 hours. The release rate is determined using the second method (paddle method) of the "Dissolution and Release Determination Method" of the 2020 edition (Volume IV) of the Chinese Pharmacopoeia, e.g., at 37°C ± 0.5°C and a paddle speed of 50 rpm in 900 mL of 0.06N hydrochloric acid solution.

[0060] In one embodiment, the release amount (cumulative dissolution rate) of the active ingredient (e.g., pregabalin) in the gastric retentive sustained-release pharmaceutical composition is less than 15% within 1 hour, 30% to 55% within 4 to 8 hours, and more than 80% within 16 hours. The release amount is determined using the second method (paddle method) of the "Dissolution and Release Determination Method" of the 2020 edition (Volume IV) of the Chinese Pharmacopoeia, such as at 37°C ± 0.5°C and a paddle speed of 50 rpm in 900 mL of pH 4.5 acetate buffer solution.

[0061] In a certain embodiment, the gastric retentive sustained-release pharmaceutical composition can be administered to patients in need by administration before meals, after meals, or before bedtime.

[0062] In a certain embodiment, the gastric retentive sustained-release pharmaceutical composition can be administered to a patient in need thereof twice a day, or once a day.

[0063] In one embodiment, the gastric retentive sustained-release pharmaceutical composition can be used to treat one or more of the following diseases:

[0064] (1) Neuropathic pain (e.g., pain caused by nerve damage); the neuropathic pain may be peripheral neuropathy pain and / or central neuropathy pain;

[0065] The peripheral neuropathy pain may be pain caused by diabetes or pain caused by herpes zoster; the central neuropathy pain may be pain caused by spinal cord injury;

[0066] (2) epilepsy; for example, partial seizures (seizures that begin in a specific part of the brain);

[0067] (3) fibromyalgia;

[0068] (4) Generalized anxiety disorder; such as long-term anxiety or tension about daily things.

[0069] The present invention also provides a gastric retention sustained-release pharmaceutical composition, which is composed of the following components:

[0070] 15 wt% to 40 wt% active ingredient; the active ingredient is pregabalin, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof;

[0071] 10 wt% to 20 wt% of a matrix forming agent; the matrix forming agent is a copolymer formed by polymerization of ethyl acrylate and methyl methacrylate;

[0072] 30 wt% to 60 wt% of a swellable polymer;

[0073] 3wt% to 10wt% gelling agent;

[0074] 2 wt% to 20 wt% porogen;

[0075] 0wt% to 10wt% lubricant;

[0076] 0wt% to 5wt% flow aid.

[0077] The types and contents of the active ingredient, the matrix forming agent, the swellable polymer, the gelling agent, the pore-forming agent, the lubricant, and the glidant are as described above.

[0078] In a certain embodiment, the gastric retention sustained-release pharmaceutical composition is composed of the following components: 29.34wt% pregabalin, 25wt% to 27wt% crospovidone, 11.5wt% to 14wt% NM 30D, 6wt%-8wt% povidone, 0.26wt% colloidal silicon dioxide, 18.5wt%-19.5wt% polyethylene oxide, 5.5wt%-5.9wt% carbomer and 0.5wt% magnesium stearate;

[0079] In a certain embodiment, the gastric retention sustained-release pharmaceutical composition is composed of the following components: 29.34wt% pregabalin, 25wt% crospovidone, 12.5wt% NM 30D, 8 wt% povidone, 0.26 wt% colloidal silicon dioxide, 18.5 wt% polyethylene oxide, 5.9 wt% carbomer, and 0.5 wt% magnesium stearate;

[0080] In a certain embodiment, the gastric retention sustained-release pharmaceutical composition is composed of the following components: 29.34wt% pregabalin, 27wt% crospovidone, 11.5wt% NM 30D, 6 wt% povidone, 0.26 wt% colloidal silicon dioxide, 19.5 wt% polyethylene oxide, 5.9 wt% carbomer, and 0.5 wt% magnesium stearate;

[0081] In a certain embodiment, the gastric retention sustained-release pharmaceutical composition is composed of the following components: 29.34wt% pregabalin, 25wt% crospovidone, 14wt% NM 30D, 7 wt% povidone, 0.26 wt% colloidal silicon dioxide, 18.5 wt% polyethylene oxide, 5.5 wt% carbomer, and 0.5 wt% magnesium stearate;

[0082] In a certain embodiment, the gastric retention sustained-release pharmaceutical composition is composed of the following components: 29.34wt% pregabalin, 25wt% crospovidone, 13.5wt% NM 30D, 7 wt% povidone, 0.26 wt% colloidal silicon dioxide, 18.5 wt% polyethylene oxide, 5.9 wt% carbomer, and 0.5 wt% magnesium stearate;

[0083] In a certain embodiment, the dosage form of the gastric retentive sustained-release pharmaceutical composition is preferably tablets, capsules, micropills, granules, powders or microtablets, more preferably tablets.

[0084] Described gastric retention type sustained-release pharmaceutical composition can be prepared by methods known in the art, for example, active ingredient and matrix forming agent, swellable polymer, gel and other pharmaceutically acceptable excipient can be directly mixed and compressed, or, in order to improve the homogeneity of product, can be merged and mixed components in stages. For example, active ingredient and one or more components in matrix forming agent, swellable polymer, gel and other pharmaceutically acceptable excipient are granulated by fluidized bed or extrusion granulation method, then mixed with all the other components. Or, active ingredient can first be mixed with one or more components in matrix forming agent, swellable polymer, gel and other pharmaceutically acceptable excipient, then mixed with other components in one or more mixing operations. If necessary, before mixing, the particle size of one or more components can be controlled by sieving or pulverizing.

[0085] The method for preparing the gastric retention sustained-release pharmaceutical composition may include the following steps:

[0086] 1) Granulating material 1 with a solution to obtain granules;

[0087] The solution is the porogen, the matrix forming agent, the flow aid and purified water; the material 1 is the active ingredient and the swellable polymer;

[0088] 2) mixing the particles obtained in step 1) with the gelling agent and the lubricant to obtain material 2;

[0089] 3) Compressing the material 2 obtained in step 2) into tablets to obtain a gastric retentive sustained-release pharmaceutical composition.

[0090] In one embodiment, in step 1), the granulation can be performed on a fluidized bed.

[0091] In one embodiment, in step 1), the inlet air temperature of the granulation is 50-75°C.

[0092] In one embodiment, in step 1), the temperature of the material 1 is 35-40°C.

[0093] In one embodiment, in step 1), the atomization pressure of the granulation is 2.0-4.0 bar.

[0094] In one embodiment, in step 1), during the granulation process, the material temperature is 20-40°C.

[0095] In one embodiment, in step 1), after the granulation, the process further comprises drying and sieving.

[0096] In one embodiment, in step 1), the drying is performed until the weight loss is ≤4%.

[0097] In one embodiment, in step 1), the sieving is performed through a 20-30 mesh sieve.

[0098] In one embodiment, in step 2), the particles obtained in step 1) are sequentially mixed with the gelling agent and the lubricant.

[0099] In one embodiment, in step 3), the size of the tabletting die is 22 mm in length and 10.8 mm in width.

[0100] The present invention also provides a film-coated tablet, which consists of a film coating and the above-mentioned gastric retentive sustained-release pharmaceutical composition, wherein the film coating is coated on the outside of the gastric retentive sustained-release pharmaceutical composition, and the gastric retentive sustained-release pharmaceutical composition is a tablet.

[0101] The film coating will not affect the release of the active ingredient due to the initial dissolution, hydration, perforation, etc. of the coating layer, and the release rate of the active ingredient in the coated pharmaceutical composition has no significant deviation compared with the non-coated pharmaceutical composition. The film coating can be selected from one or more suitable coating materials known in the art, including but not limited to hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl cellulose, povidone, etc. The film coating can also contain one or more components of plasticizers, colorants, and light-shielding agents. Among them, the plasticizer can be selected from propylene glycol, polyethylene glycol, glycerol, glycerol monoacetate, glycerol triacetate, castor oil, acetylated glycerides, phthalates, etc., the colorant can be selected from commonly used water-soluble pigments, water-insoluble pigments and lake dyes, etc., and the light-shielding agent can be selected from titanium dioxide. Commercially available film coatings can also be used directly, including but not limited to and Preferred The coating material may be applied using any conventional coating technique known in the art, such as in a conventional coating pan or fluid bed processor.

[0102] The present invention also provides a use of the above-mentioned gastric retentive sustained-release pharmaceutical composition or the above-mentioned film-coated tablet in the preparation of a medicament for treating one or more of the following diseases:

[0103] (1) Neuropathic pain (e.g., pain caused by nerve damage); the neuropathic pain may be peripheral neuropathy pain and / or central neuropathy pain;

[0104] The peripheral neuropathy pain may be pain caused by diabetes or pain caused by herpes zoster; the central neuropathy pain may be pain caused by spinal cord injury;

[0105] (2) epilepsy; for example, partial seizures (seizures that begin in a specific part of the brain);

[0106] (3) fibromyalgia;

[0107] (4) Generalized anxiety disorder; such as long-term anxiety or tension about daily things.

[0108] abbreviation:

[0109] h: hour

[0110] min: minutes

[0111] s: seconds

[0112] mm: millimeters

[0113] nm: nanometer

[0114] mL: milliliters

[0115] μL: microliter

[0116] μm: micrometer

[0117] rpm: revolutions per minute

[0118] API: Active Pharmaceutical Ingredient

[0119] HPLC: High Performance Liquid Chromatography

[0120] w / w: weight (mass) / total weight (mass)

[0121] bar: Bar

[0122] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0123] The reagents and raw materials used in the present invention are commercially available.

[0124] The positive progress effect of the present invention is:

[0125] 1. The pregabalin sustained-release composition of the present invention can achieve gastric retention under conditions of normal gastric acid secretion, gastric acid deficiency or insufficient secretion, thereby allowing for stable drug release;

[0126] 2. Improve drug stability and reduce the risk of lactam impurities. DETAILED DESCRIPTION

[0127] The present invention is further illustrated by way of examples below, but the invention is not limited to the scope of the examples. Experimental methods in the following examples, where specific conditions are not specified, were performed according to conventional methods and conditions, or according to commercial specifications. Unless otherwise specified, all reagents and materials used in the present invention were obtained from public commercial sources.

[0128] 1. The in vitro dissolution test method of the pharmaceutical composition of the present invention is as follows:

[0129] According to the second method (paddle method) of the "Dissolution and Release Determination Method" of the 2020 edition of the Chinese Pharmacopoeia (Volume IV), the amount of API released from a sample of the pharmaceutical composition immersed in 900 mL of an aqueous dissolution medium (0.06 N hydrochloric acid solution or acetate buffer at pH 4.5) was determined at 37°C ± 0.5°C and a paddle speed of 50 rpm. Typically, 10 mL of the dissolution solution was removed at 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, and 24 hours, filtered, and used as the test solution. The solution was immediately replenished with the dissolution medium at the same temperature and compatible volume, and analyzed by HPLC under the following conditions: detection instrument: Agilent 1260 II liquid phase; chromatographic column: Gemini C18; methanol-phosphate buffer (pH 6.3 ± 0.05) (35:65) as the mobile phase; detection wavelength: 210 nm; run time: 5 minutes.

[0130] 2. The method for detecting the swelling degree of the pharmaceutical composition of the present invention is as follows:

[0131] The drug sample was placed in a 0.06N hydrochloric acid medium (simulating a normal gastric acid environment) or a pH 6.0 medium (simulating a gastric acid environment when the gastric acid is deficient or insufficient) at a constant temperature of 37°C. Starting from 0 min after addition, the initial bleaching time was recorded. The drug sample was regularly removed from the dissolution medium, and the swelling diameter of the sample was detected using a vernier caliper.

[0132] Preparation of pH 6.0 medium: Take 6.8g of potassium dihydrogen phosphate, add 28mL of 0.2mol / L sodium hydroxide aqueous solution (take 8.0g of sodium hydroxide, dissolve it in water and dilute it to 1000mL) and an appropriate amount of water to dissolve, then add water to dilute it to 1000mL, shake well, and the solution is obtained.

[0133] 3. The method for detecting the rigidity of the pharmaceutical composition of the present invention is as follows:

[0134] The drug samples were placed in a 0.06N hydrochloric acid medium (simulating a normal gastric acid environment) or a pH 6.0 medium (simulating a gastric acid environment when the gastric acid is deficient or insufficient, and the preparation method is consistent with that for the swelling test) at a constant temperature of 37°C. The drug samples were taken out regularly and their rigidity was tested under the following set conditions: an SMS texture analyzer equipped with a P / 0.25S ball probe; the settings were: a 5kg load cell, a 2.0g trigger force, a 0.2mm / s test speed, and an 8mm distance.

[0135] 4. The detection method of related substances in the pharmaceutical composition of the present invention is as follows:

[0136] According to the high performance liquid chromatography method 0512 of the fourth part of the Chinese Pharmacopoeia 2020 edition, the HPLC detection instrument was Agilent 1260 II liquid phase; the chromatographic column was GL Sciences Inertsil ODS-3V; 0.02 M diammonium hydrogen phosphate solution (pH 5.9): methanol (90:10) was used as the mobile phase A, and acetonitrile: methanol (90:10) was used as the mobile phase B, and the gradient elution was 98% A / 2% B→77% A / 23% B→30% A / 70% B→98% A / 2% B for a total of 50 minutes; the detection wavelength was 210 nm.

[0137] The present invention uses Lyrica CR (330 mg, batch number: DN5396), a pregabalin tablet produced by Pfizer Inc. of the United States, as a control preparation.

[0138] Example 1: Preparation of Pregabalin Gastric Floating Sustained-Release Tablets

[0139] According to the prescription in Table 1, tablets weighing 1125 mg were prepared using the following preparation process:

[0140] 1) mixing the active ingredient and the swellable polymer crospovidone;

[0141] 2) Solution preparation: mixing the porogen, matrix former, flow aid and purified water to prepare a solution;

[0142] 3) Fluidized bed granulation: The material obtained in step 1) is added to a fluidized bed, the inlet air temperature is set at 50-75°C, and the inlet air volume is adjusted to ensure that the granules are in a well-fluidized state. After the material is preheated to 35-40°C, the atomization pressure is adjusted to 2.0-4.0 bar, and the solution prepared in step 2) is sprayed into the fluidized bed for granulation. The material temperature is monitored and maintained at 20-40°C during the granulation process. After the granulation is completed, the material is dried until the drying loss is ≤4%, and the machine is stopped and the granules are discharged. The dried granules are sieved through a 20-30 mesh sieve for later use.

[0143] 4) mixing the granules obtained in step 3) with the materials other than the lubricant for 5 minutes, then adding the lubricant and mixing for a total of 5 minutes;

[0144] 5) The material obtained in step 4) was tableted, and the tableting die size was: length 22 mm × width 10.8 mm.

[0145] Table 1

[0146]

[0147] *Note: 1. RL PO and The glass transition temperature of L100-55 is relatively high, so a plasticizer needs to be added to the composition.

[0148] 2. RL PO means RL in powder form;

[0149] 1.1 Swelling and rigidity of tablets in 0.06N hydrochloric acid medium

[0150] (a) Tablet swelling

[0151] The tablet volume swelling rate was measured in 0.06N hydrochloric acid solution, and its length, width, and thickness were physically measured at 1 h, 2 h, 4 h, and 6 h. The results are shown in Table 2.

[0152] Table 2

[0153]

[0154] Note: “-” means not tested;

[0155] (b) Tablet rigidity

[0156] The relationship between tablet rigidity (g.mm) and time (h) in 0.06N hydrochloric acid medium is shown in Table 3.

[0157] Table 3

[0158] rigidity Control preparation Composition F1 Composition F2 Composition F3 Composition F4 Composition F5 1h 3564.96 6198.37 2602.61 2410.21 3241.49 >6000 2h 2635.85 6129.37 - 2345.63 2844.96 3645.29 4h 1710.49 3896.86 760.73 1073.06 2579.76 - 6h 1647.91 2280.46 - - 2274.91 -

[0159] Note: “-” means not tested;

[0160] As shown in Table 2, compositions F1 to F3 all swelled rapidly and floated significantly faster than the control formulation, demonstrating strong swelling and excellent buoyancy. Composition F4 floated more slowly but exhibited superior swelling performance. However, composition F5 struggled to float, and its swollen volume decreased rapidly over time. This made it difficult for the tablet to expand to a volume sufficient to prevent expulsion from the pylorus, preventing gastric retention.

[0161] Although compositions F2 and F3 have good swelling properties, as can be seen from Table 3, the rigidity of compositions F2 and F3 in 0.06N hydrochloric acid medium is relatively low, and the rigidity shows a significant downward trend after 4 hours, which will greatly increase the risk of rapid excretion of the tablet from the pylorus.

[0162] 1.2 Swelling and rigidity of tablets in pH 6.0 medium

[0163] Composition F1 and composition F4 both have good swelling properties and rigidity in a 0.06N hydrochloric acid medium. However, in order to simulate the higher gastric pH environment of patients with gastric achlorhydria or hyposecretion, the swelling properties and rigidity of composition F1 and composition F4 were further tested in a pH 6.0 medium.

[0164] (a) Tablet swelling

[0165] The tablet volume swelling rate was measured in a medium at pH 6.0. The results are shown in Table 4.

[0166] Table 4

[0167]

[0168] (b) Tablet rigidity

[0169] The relationship between tablet rigidity (g.mm) and time (h) in pH 6.0 medium is shown in Table 5.

[0170] Table 5:

[0171] time Control preparation Composition F1 Composition F4 1h 3175.30 3254.47 4634.85 2h 2741.89 3214.23 2348.85 4h 1844.68 2158.83 1638.83 6h 1675.58 1306.04 1056.16

[0172] As shown in Tables 4 and 5, composition F1 maintained good swelling and rigidity in a pH 6.0 medium. While composition F4 exhibited good swelling, its rigidity had already significantly decreased by 2 hours, and the overall rate of rigidity decline was rapid over time, reaching a level significantly lower than that of the control formulation at 6 hours. This increases the risk of rapid excretion of the tablet in patients with achlorhydria, preventing gastric retention. Composition F1, on the other hand, exhibited excellent gastric retention properties even at a higher gastric pH. These results demonstrate that the compositions of the present invention can achieve rapid floating and swelling in the stomach while maintaining excellent rigidity, achieving gastric retention, regardless of whether gastric acid secretion is normal or achlorhydria or hyposecretion.

[0173] Example 2

[0174] Compositions F6 to F9 were prepared using the same preparation process as in Example 1.

[0175] Table 6

[0176]

[0177] The swelling degrees of compositions F6 to F9 were tested in a 0.06N hydrochloric acid medium. The results are shown in Table 7.

[0178] Table 7

[0179]

[0180]

[0181] Note: “ / ” indicates that the test was terminated due to insufficient rigidity;

[0182] The rigidity of compositions F6 to F9 was tested in a 0.06N hydrochloric acid medium. The results are shown in Table 8.

[0183] Table 8

[0184] time Control preparation Composition F6 Composition F7 Composition F8 Composition F9 1h 3564.96 2389.66 5502.73 >6000 5944.85 2h 2635.85 1588.94 4787.93 5474.18 4288.06 4h 1710.49 814.95 3524.38 2371.00 3856.40 6h 1647.91 / 1980.10 1440.48 2156.00

[0185] Note: “ / ” indicates that the test was terminated due to insufficient rigidity;

[0186] It can be seen from Table 7 and Table 8 that compositions F6 to F9 can swell well, but when When the proportion of NM 30D is too low, the rigidity of the composition F6 decreases significantly over time. When the proportion of NM 30D is greater than 30D, the tablets show excellent swelling and rigidity properties, which allows the drug to expand rapidly when entering the stomach and makes it possible for the drug to stay in the stomach for a longer time.

[0187] The dissolution rates of compositions F1 and F7 to F9 were tested in 0.06N hydrochloric acid. The results are shown in Table 9.

[0188] Table 9

[0189] Time (h) Control preparation Composition F1 Composition F7 Composition F8 Composition F9 0 0.0 0.0 0.0 0.0 0.0 1 23.8 18.4 19.8 20.0 19.8 2 36.4 29.8 30.8 30.4 30.6 4 51.8 46.1 46.4 45.2 46.2 6 62.9 58.9 58.8 56.8 58.5 8 72.0 69.4 68.8 66.0 68.6 10 78.7 78.1 77.3 73.7 76.8 12 84.4 85.3 84.5 81.0 84.2 16 92.8 95.8 95.1 90.8 94.6 24 98.7 103.3 103.5 96.7 102.5

[0190] The dissolution rates of compositions F1 and F9 were tested in a medium at pH 4.5. The results are shown in Table 10.

[0191] Table 10

[0192] Time (h) Control preparation Composition F1 Composition F9 0 0.0 0.0 0.0 1 15.8 11.0 9.2 2 23.4 19.3 17.4 4 35.3 32.9 30.8 6 45.0 44.4 42.2 8 52.7 54.7 52.4 10 59.9 64.0 62.0 12 66.5 72.0 70.2 16 76.3 85.0 83.6 24 89.4 98.7 99.7

[0193] As shown in Table 9, in 0.06N hydrochloric acid, compositions F1 and F7-F9 all effectively controlled drug release, with release profiles similar to those of the control formulation. In pH 4.5, compositions F1 and F9 also exhibited excellent sustained-release patterns.

[0194] The above examples demonstrate that the composition of the present invention exhibits rapid buoyancy independent of gastric pH, excellent swelling properties, and rigidity, enabling prolonged gastric retention while simultaneously achieving sustained drug release. This approach leverages pregabalin's unique absorption site and absorption window to achieve both sustained release and absorption, while also fully addressing the dosing needs of pregabalin for patients with varying gastric pH levels due to factors such as race, age, disease, diet, and medication use.

[0195] Example 3: Stability Study

[0196] The prepared tablets were packaged in oral solid pharmaceutical high-density polyethylene bottles (100 mL), placed at 40° C. and 75% relative humidity for stability testing, and the lactam content was analyzed by HPLC. The results are shown in Table 11.

[0197] Table 11

[0198]

[0199] Note: “ / ” means not tested.

[0200] As shown in the results of Table 11, the pharmaceutical compositions F1 and F9 of the present invention exhibited excellent stability, comparable to the control formulation, and effectively inhibited the generation rate of lactam impurities. However, the lactam impurity content of RL PO increased significantly after 10 days of storage, indicating a significant decrease in stability.

Claims

1. A gastric retentive sustained-release pharmaceutical composition comprising the following components: 25 wt% to 30 wt% active ingredient; the active ingredient is pregabalin, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof; 11wt% to 14wt% matrix forming agent; the model of the matrix forming agent is Copolymer of NM 30D; 40 wt% to 50 wt% of a swellable polymer; the swellable polymer comprises 25 wt% to 27 wt% of crospovidone and 18.5 wt% to 19.5 wt% of polyethylene oxide; 5wt% to 6wt% gelling agent; the gelling agent is carbomer; 5wt% to 10wt% of a porogen; the porogen is povidone; 0.2wt% to 2wt% lubricant; the lubricant is magnesium stearate; 0.1wt% to 2wt% of a flow aid; the flow aid is colloidal silicon dioxide; The wt% refers to the mass proportion of the component in the gastric retention sustained-release pharmaceutical composition.

2. The gastric retentive sustained-release pharmaceutical composition according to claim 1, wherein The gastric retention sustained-release pharmaceutical composition contains 29.34 wt% of the active ingredient.

3. The gastric retentive sustained-release pharmaceutical composition according to claim 1, wherein The gastric retention sustained-release pharmaceutical composition contains 11.5 wt% to 14 wt% of the matrix forming agent.

4. The gastric retentive sustained-release pharmaceutical composition according to claim 1, wherein The gastric retention sustained-release pharmaceutical composition contains 43.5 wt% to 46.5 wt% of the swellable polymer.

5. The gastric retentive sustained-release pharmaceutical composition according to claim 1, wherein The gastric retention sustained-release pharmaceutical composition contains 5.5 wt% to 5.9 wt% of the gel.

6. The gastric retentive sustained-release pharmaceutical composition according to claim 1, wherein The gastric retention sustained-release pharmaceutical composition contains 6wt% to 8wt% of the pore-forming agent.

7. The gastric retentive sustained-release pharmaceutical composition according to claim 1, wherein The dosage form of the gastric retention sustained-release pharmaceutical composition is tablets, capsules, pellets, granules or powders.

8. The gastric retentive sustained-release pharmaceutical composition according to claim 7, wherein The dosage form of the gastric retention sustained-release pharmaceutical composition is tablets.

9. The gastric retentive sustained-release pharmaceutical composition according to claim 1, wherein The dosage form of the gastric retention sustained-release pharmaceutical composition is a microtablet.

10. A film-coated tablet, comprising a film coating and the gastric retentive sustained-release pharmaceutical composition according to any one of claims 1 to 6, wherein the film coating is coated on the outside of the gastric retentive sustained-release pharmaceutical composition, and the gastric retentive sustained-release pharmaceutical composition is a tablet.

11. Use of the gastric retentive sustained-release pharmaceutical composition according to any one of claims 1 to 9 or the film-coated tablet according to claim 10 in the preparation of a medicament for treating one or more of the following diseases: (1) neuropathic pain; (2) epilepsy; (3) fibromyalgia; (4) generalized anxiety disorder.

Images