WO2023279381A1 - Pharmaceutical composition of pregabalin, preparation method therefor and use thereof - Google Patents

Pharmaceutical composition of pregabalin, preparation method therefor and use thereof Download PDF

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Publication number
WO2023279381A1
WO2023279381A1 PCT/CN2021/105518 CN2021105518W WO2023279381A1 WO 2023279381 A1 WO2023279381 A1 WO 2023279381A1 CN 2021105518 W CN2021105518 W CN 2021105518W WO 2023279381 A1 WO2023279381 A1 WO 2023279381A1
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Prior art keywords
pregabalin
pharmaceutical composition
preparation
pharmaceutically acceptable
release
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PCT/CN2021/105518
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French (fr)
Chinese (zh)
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郭桢
王璇
董睿
王婷婷
应述欢
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上海博志研新药物研究有限公司
上海博志研新药物技术有限公司
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Priority to PCT/CN2021/105518 priority Critical patent/WO2023279381A1/en
Publication of WO2023279381A1 publication Critical patent/WO2023279381A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the invention belongs to the field of pharmaceutical preparations, and in particular relates to a pharmaceutical composition of pregabalin, especially a pharmaceutical composition of pregabalin, a preparation method and application thereof.
  • Pregabalin is a gamma-aminobutyric acid (GABA) analog developed by Pfizer (trade name Lyrica), which has been approved by the FDA for adults with partial-onset diabetic peripheral neuralgia, postherpetic neuralgia, muscle fiber Adjunctive treatment of neuropathic pain caused by pain and spinal cord injury. In addition, it is also approved for the adjunctive treatment of partial-onset epilepsy in patients with epilepsy 4 years of age and older.
  • GABA gamma-aminobutyric acid
  • domestically sold pregabalin preparations include Pfizer's Lyrica immediate-release capsules (25, 50, 75, 100, 150, 200, 300mg specifications) and Chongqing Saiwei Pharmaceutical Co., Ltd.'s immediate-release capsules (25, 75, 100mg), both need to be administered 2 to 3 times a day.
  • pregabalin is a class I drug of the BCS classification system. It reaches its peak concentration 1.5 hours after oral administration, and its relative bioavailability is ⁇ 90%. Poor compliance. However, if the drug is taken QD (once a day), it can not only improve the patient's compliance, but also reduce the C max of the drug in the blood, reduce or avoid the potential, undesired side effects related to the dosage, and can increase the C max of the drug in the plasma. The lowest concentration of C min increases drug efficacy.
  • pregabalin in the gastrointestinal tract is heterogeneous, it is absorbed in the small intestine and ascending colon, but it is rarely absorbed in intestinal segments other than the hepatic flexure of the colon, which means that the average pregabalin
  • the absorption window is on average about 6 hours or less. Therefore, the drug released in the existing immediate-release dosage form or sustained-release dosage form after about 6 hours cannot be absorbed by the human body, resulting in a large waste of medicine.
  • Patent document CN103040785A relates to a pregabalin osmotic gastric-retentive tablet, which makes the osmotic gastric-retentive tablet stay in the stomach for a long time and achieve zero-order release through expansion and osmotic pump principles.
  • this invention is a perforated osmotic pump preparation, which has high requirements for laser or other mechanical perforation equipment.
  • the release of drugs from single-sided or double-sided drug release holes may cause side effects caused by excessive local drug concentration, while drug release holes Blockage can easily cause drug release.
  • Patent document CN103702664A relates to a pregabalin sustained-release tablet of a two-phase controlled-release system, which is prepared by a wet granulation process.
  • pregabalin is easily soluble in water, and 50% HPC alcohol solution is selected as the binder in the wet granulation process of the invention, it is easy to cause mold sticking during the tableting process, resulting in rough or flawed edges of the tablet ,
  • it is easy to cause mold sticking during the tableting process, resulting in rough or flawed edges of the tablet significantly affect the quality of sustained-release tablets, not only difficult to industrialized production, and the consistency of the product is also difficult to meet regulatory requirements.
  • Patent document CN104906064A relates to gastric floating sustained-release tablets containing pregabalin, which believes that there are many disadvantages in water-swellable drugs, such as damage to the gastrointestinal mucosa at the edge of the tablet, and easy accumulation in the stomach. For this reason, this document makes the surface of the tablet hydrated to form a gel by using a hydrophilic polymer material and a swelling agent, so that the volume expands, and then floats on the gastric juice to prolong the residence time in the stomach.
  • the floating of the gastric floating sustained-release tablet in the stomach requires a large amount of gastric juice, and has high requirements on the density of gastric content and the pH of gastric juice, and the individual differences of patients will significantly affect the floating effect.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the following components:
  • the active ingredient can be in any pharmaceutically acceptable form of pregabalin, for example, one or two selected from pregabalin, its pharmaceutically acceptable salt, complex, solvate or polymorph. species or more.
  • the content of the active ingredient is calculated as pregabalin.
  • the pharmaceutically acceptable salt of pregabalin may include a pharmaceutically acceptable salt, including a half-salt, of pregabalin with an organic acid, an inorganic acid, an organic base or an inorganic base.
  • the pharmaceutically acceptable salt may be one, two or more selected from pregabalin hydrochloride, hydrobromide, bisulfate, sodium salt, potassium salt, magnesium salt and the like.
  • a solvate of pregabalin means pregabalin and stoichiometric or non-stoichiometric amounts of one, two or more pharmaceutically acceptable solvent molecules (e.g. alcohols such as ethanol, water, or mixture) molecular complexes.
  • solvent molecules e.g. alcohols such as ethanol, water, or mixture
  • the weight percentage content of the at least one active ingredient selected from pregabalin, its pharmaceutically acceptable salt or solvate can be 5-40%, such as 5%, 10% , 15%, 20%, 25%, 30%, 35% or 40%.
  • the skeleton material may be selected from hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyacrylic acid resin, carbomer, polyvinyl acetate povidone mixture, hydroxyethyl cellulose, ethyl One, two or more of cellulose, polyvinyl alcohol, and polyoxyethylene.
  • the weight percentage content of the skeleton material can be 10-60%, such as 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% %, 55% or 60%.
  • the expansion agent may be selected from cross-linked polyvinylpyrrolidone (crospovidone), cross-linked sodium carboxymethylcellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, One, two or more of carmellose calcium, carmellose, and polacrilin potassium.
  • crospovidone cross-linked polyvinylpyrrolidone
  • sodium carboxymethylcellulose sodium carboxymethyl starch
  • low-substituted hydroxypropyl cellulose One, two or more of carmellose calcium, carmellose, and polacrilin potassium.
  • the weight percentage content of the bulking agent can be 1-25%, such as 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20% or 25% %.
  • the filler may be selected from one, two or more of lactose, starch, mannitol, microcrystalline cellulose, and calcium hydrogen phosphate.
  • the weight percentage content of the filler can be 0-20%, such as 0% or higher than 0% and not more than 20%, such as 1%, 2%, 3%, 4%. , 5%, 10%, 15% or 20%.
  • the lubricant may be selected from one, two or more of talcum powder, magnesium stearate, and micronized silica gel.
  • the weight percent content of the lubricant can be 0.5-5%, such as 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5% % or 5.0%.
  • the pharmaceutical composition may be a preparation (such as a tablet), for example, a gastric-floating sustained-release preparation of pregabalin, preferably a pregabalin gastric-floating sustained-release tablet.
  • the pharmaceutical composition may further include a coating covering the outer surface of the above-mentioned components.
  • the present invention also provides a preparation method of the pharmaceutical composition, comprising mixing the above components.
  • the preparation method includes uniformly mixing the active ingredient, skeleton material, expansion agent and filler, and then adding a lubricant.
  • the preparation method further includes mixing the above-mentioned components, and then preparing the obtained mixture into a preparation, for example, preparing a tablet through a compression step and an optional coating step.
  • composition of the present invention it is used for treating or preventing postherpetic neuralgia.
  • the present invention also provides a method for treating or preventing postherpetic neuralgia, comprising administering the above pharmaceutical composition to a patient in need.
  • the present invention also provides a method for reducing the frequency of medication for patients, comprising administering the above pharmaceutical composition to patients in need, such as patients with postherpetic neuralgia.
  • the frequency of dosing by the patient is at most one dose per day.
  • the present invention also provides a method for improving patients' medication compliance, comprising administering the above pharmaceutical composition to patients in need, such as patients with postherpetic neuralgia.
  • the present invention also provides the use of the above-mentioned pharmaceutical composition for preparing a medicament, wherein the medicament is used for treating or preventing postherpetic neuralgia.
  • the drug release performance of the pharmaceutical composition of the present invention is excellent. In the in vitro dissolution test, it releases 25%-40% in the 2nd hour, 40%-50% in the 4th hour, 55%-65% in the 6th hour, and more than 80% in the 12th hour. It can release the drug stably. Conform to Chinese Pharmacopoeia standard.
  • the coating layer of the pharmaceutical composition of the present invention further improves the stability of the drug, masks the bitter taste of the active ingredient, and the coating layer has no obvious influence on the release rate of the tablet.
  • the pharmaceutical composition of the present invention can be prepared as a gastric-floating sustained-release tablet of pregabalin once a day, and the gastric-retentive tablet has excellent swelling and floating properties in the stomach, thereby realizing the delayed release of pregabalin It can effectively prolong the residence time of pregabalin in the stomach and upper small intestine, improve bioavailability, obtain stable blood drug concentration, and reduce the frequency of administration.
  • the pharmaceutical composition of the present invention can hydrate and expand in the stomach to a size with a width greater than 13 mm after being taken by a patient.
  • the sustained-release tablet after the sustained-release tablet contacts the gastric juice, its density is lower than that of the gastric juice, so it quickly floats on the upper part of the gastric juice, and the floating time can last up to more than 24 hours, achieving the effect of gastric retention and improving bioavailability.
  • the sustained-release tablet has larger swelling size and stronger gel strength, thereby reducing individual differences under different physiological conditions.
  • the excipients of the pharmaceutical composition of the present invention have good fluidity and strong anti-adhesive properties, and can be directly compressed to obtain pregabalin gastric retention sustained-release tablets after mixing.
  • the process is simple and easy, the cost is low, and it is suitable for industrial production.
  • Pregabalin was provided by Orient Pharmaceutical Co., Ltd. with a purity of 99.2%;
  • Crospovidone (PVPP) and polyvinyl acetate povidone blend (KSR) are available from BASF under the tradenames and in Nominal 80/19 (w/w) mixture of PVAc and PVP;
  • HEC Hydroxyethyl cellulose
  • Natrosol TM Hydroxyethyl cellulose
  • Mv molecular weight in the range of about 9 ⁇ 10 4 to 13 ⁇ 10 5 (Mv), such as HEC (HX Pharm), HEC (M Pharm );
  • Ethylcellulose is available from Ashland under the trade name Aqualon TM , with a molecular weight in the range of 75000 to 215000 (Mv) and a Brookfield viscosity in the range of 8 to 105 mPa.s, such as EC (T10 Pharm);
  • Polyacrylic acid resin is a cationic or anionic copolymer obtained by polymerization of dimethylaminoethyl methacrylate, methacrylic acid, and methacrylate in different proportions. It can be obtained from Rohm, Germany, and its trade name is
  • Hypromellose can be obtained from IFF Company, its trade name is METHOCEL TM , and the model can be selected from K100LV, K4M and K100M;
  • SRP 80 is a functional excipient based on the hydrophilic polymer polyvinyl alcohol (PVA), containing only a single component - PVA 40-88*, without any other additives, available from Merck;
  • PVA polymer polyvinyl alcohol
  • Polyethylene oxide is available from DOW Corporation under the trade name POLYOX TM , and its molecular weight is in the range of about 9 ⁇ 10 5 to 7 ⁇ 10 6 (Mv);
  • Carbomer is available from RITA under the trade name Available from Lubrizol under the tradename
  • the viscosity range can be selected from 4000 to 39400cPs, such as Carbomer 971P;
  • Carmellose calcium (CMC-Ca) can be obtained from Bolak Company, and the particle size range can be selected from 90 to 250 mesh;
  • the lubricant can be selected from one, two or more of talcum powder, magnesium stearate, and micronized silica gel, wherein magnesium stearate can be obtained from Anhui Shanhe;
  • the filler can be selected from one, two or more of lactose, starch, mannitol, microcrystalline cellulose, and calcium hydrogen phosphate.
  • lactose can be obtained from MEGGLE
  • microcrystalline cellulose can be obtained from Riddenmayer (Shanghai) Fiber Trading Co., Ltd.
  • This product is a film-coated tablet available from Colorcon as series.
  • Examples 1 to 24 Pharmaceutical compositions containing pregabalin
  • the active ingredients and auxiliary materials except magnesium stearate were mixed in a three-dimensional motion mixer for 20 minutes, and then magnesium stearate was added and mixed for 5 minutes to obtain the final mixture.
  • magnesium stearate was added and mixed for 5 minutes to obtain the final mixture.
  • a rotary tablet press 22.0 ⁇ 10.9mm almond-shaped punched into tablets, and coated.
  • the film coating premix manufacturer is Colorcon
  • the model is 85F140030-CN.
  • Example 8 Pregabalin 30 30 Polyvinyl acetate povidone blend 40 40 MCC 102 55 55 CMC-Ca 15 15 PEO WSR N60K 6 the PEO WSR Coagulat the 6 Carbomer 971P 3 3 Magnesium stearate 1 1
  • Example 15 Example 16
  • Example 17 Pregabalin 30
  • 30 Polyvinyl acetate povidone blend 40
  • 40 CMC-Ca 10 17
  • 20 PEO WSR N60K 14
  • the Carbomer 971P 5 4 3
  • the fluidity of the material is judged by the result of the Carr index, and the evaluation method is as follows:
  • the present invention adopts the pregabalin sustained-release tablet (330mg) produced by Pfizer Pharmaceutical Co., Ltd. of the United States as a control example.
  • the composition of the sustained-release tablet is: containing 330 mg of active ingredient pregabalin, and other components include polyvinyl acetate povidone mixture, cross-linked povidone, polyoxyethylene, carbomer and magnesium stearate.
  • two other batches were used, which are respectively counted as comparative example 1 and comparative example 2.
  • the pregabalin formulations prepared according to the present invention exhibit excellent sustained-release dissolution patterns.
  • the prepared pregabalin sustained-release preparation has basically no burst release effect in 1 hour, the dissolution rate is 50% to 70% in 8 hours, and the release rate exceeds 80% in 16 hours.
  • the cumulative dissolution rate of the tablets in the comparative example was about 20% in 1 hour, showing a certain burst release effect, while the tablet prepared according to the present invention significantly weakened this burst release effect, making pregabalin release in a more gradual manner, Increased the safety of medication.
  • the tablets prepared by the present invention As shown in Table 13, compared with the tablets in Comparative Examples, the tablets prepared by the present invention (Example 13 and Example 15) have better rigidity after swelling for 24 hours, showing good gastric retention characteristics, and effectively controlling drug release. , improve bioavailability.

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Abstract

The present invention relates to a pharmaceutical composition of pregabalin or a pharmaceutically acceptable salt thereof, a preparation method therefor and a use thereof. The pharmaceutical composition provided comprises an active ingredient, a skeletal material, an expanding agent, a filler and a lubricant, wherein the active ingredient may be any pharmaceutically acceptable form of pregabalin. The pharmaceutical composition has excellent drug release performance, as well as excellent swelling and floating properties in the stomach, thereby achieving the characteristic of delayed pregabalin release, and the retention time of pregabalin at the upper end of the stomach and small intestine can be effectively prolonged, improving bioavailability, obtaining a stable drug concentration in the blood, and reducing the number of administration times.

Description

普瑞巴林的药物组合物及其制备方法和用途Pharmaceutical composition of pregabalin and its preparation method and application 技术领域technical field
本发明属于药物制剂领域，具体涉及普瑞巴林的药物组合物，尤其是普瑞巴林的药物组合物及其制备方法和用途。The invention belongs to the field of pharmaceutical preparations, and in particular relates to a pharmaceutical composition of pregabalin, especially a pharmaceutical composition of pregabalin, a preparation method and application thereof.
背景技术Background technique
普瑞巴林是由辉瑞开发(商品名Lyrica)的γ-氨基丁酸(GABA)类似物，已被FDA批准用于成年人部分性发作糖尿病性外周神经痛、带状疱疹后遗神经痛、肌纤维痛和脊髓损伤引起的神经病理性疼痛的辅助治疗。另外，其也被批准用于4岁及以上癫痫患者辅助治疗部分发作性癫痫。目前，国内销售的普瑞巴林制剂有辉瑞公司的乐瑞卡速释胶囊(25、50、75、100、150、200、300mg规格)以及重庆赛维药业有限公司的速释胶囊(25、75、100mg规格)，均需一日给药2～3次。Pregabalin is a gamma-aminobutyric acid (GABA) analog developed by Pfizer (trade name Lyrica), which has been approved by the FDA for adults with partial-onset diabetic peripheral neuralgia, postherpetic neuralgia, muscle fiber Adjunctive treatment of neuropathic pain caused by pain and spinal cord injury. In addition, it is also approved for the adjunctive treatment of partial-onset epilepsy in patients with epilepsy 4 years of age and older. At present, domestically sold pregabalin preparations include Pfizer's Lyrica immediate-release capsules (25, 50, 75, 100, 150, 200, 300mg specifications) and Chongqing Saiwei Pharmaceutical Co., Ltd.'s immediate-release capsules (25, 75, 100mg), both need to be administered 2 to 3 times a day.
Figure PCTCN2021105518-appb-000001
Figure PCTCN2021105518-appb-000001
研究表明，普瑞巴林为BCS分类系统I类药物，口服后1.5h达到峰浓度，相对生物利用度≥90％，若每日给药多次会导致药物的血药浓度产生明显波动，且患者顺应性差。但如QD(每天一次)服药，则不仅可提高患者的依从性，还可降低药物在血液中的C max，减轻或避免潜在、不希望的与计量有关的副作用，并可通过增加在血浆中的最低浓度C min增加药物功效。 Studies have shown that pregabalin is a class I drug of the BCS classification system. It reaches its peak concentration 1.5 hours after oral administration, and its relative bioavailability is ≥90%. Poor compliance. However, if the drug is taken QD (once a day), it can not only improve the patient's compliance, but also reduce the C max of the drug in the blood, reduce or avoid the potential, undesired side effects related to the dosage, and can increase the C max of the drug in the plasma. The lowest concentration of C min increases drug efficacy.
临床研究表明，普瑞巴林在胃肠道的吸收是不均一的，其在小肠和升结肠中被吸收，但很少在结肠肝曲以外的肠段被吸收，这意味着普瑞巴林的平均吸收窗平均约为6小时甚至更短。因此，现有的速释剂型或缓释剂型在约6小时后的药物释放无法被人体吸收，导致药物大幅浪费。Clinical studies have shown that the absorption of pregabalin in the gastrointestinal tract is heterogeneous, it is absorbed in the small intestine and ascending colon, but it is rarely absorbed in intestinal segments other than the hepatic flexure of the colon, which means that the average pregabalin The absorption window is on average about 6 hours or less. Therefore, the drug released in the existing immediate-release dosage form or sustained-release dosage form after about 6 hours cannot be absorbed by the human body, resulting in a large waste of medicine.
尽管人们试图设计能较长时间滞留在胃部或肠道前段，且能持续平稳释放药物的普瑞巴林缓释制剂，但现有制剂均存在种种缺陷：Although people try to design a pregabalin sustained-release preparation that can stay in the stomach or the front part of the intestinal tract for a long time and can release the drug continuously and steadily, there are various defects in the existing preparations:
专利文献CN103040785A涉及一种普瑞巴林渗透胃滞留片，通过膨胀和渗透泵原理，使渗透胃滞留片在胃中长时间滞留并实现零级释放。但该发明为打孔渗透泵制剂，对激 光或者其他的机械打孔设备具有较高的要求，单面或双面释药孔释放药物可能引起局部药物浓度过高产生的副作用，而释药孔堵塞易造成药物无法释放。Patent document CN103040785A relates to a pregabalin osmotic gastric-retentive tablet, which makes the osmotic gastric-retentive tablet stay in the stomach for a long time and achieve zero-order release through expansion and osmotic pump principles. However, this invention is a perforated osmotic pump preparation, which has high requirements for laser or other mechanical perforation equipment. The release of drugs from single-sided or double-sided drug release holes may cause side effects caused by excessive local drug concentration, while drug release holes Blockage can easily cause drug release.
专利文献CN103702664A涉及一种两相控释系统的普瑞巴林缓释片，通过湿法制粒工艺制备。但由于普瑞巴林易溶于水，且该发明的湿法制粒工艺中选用50％HPC醇溶液作为粘合剂，在压片过程中易导致黏模，致使片剂的边缘粗糙或有缺痕，严重影响缓释片质量，不仅难于工业化生产，且产品的一致性也难以满足监管要求。Patent document CN103702664A relates to a pregabalin sustained-release tablet of a two-phase controlled-release system, which is prepared by a wet granulation process. However, since pregabalin is easily soluble in water, and 50% HPC alcohol solution is selected as the binder in the wet granulation process of the invention, it is easy to cause mold sticking during the tableting process, resulting in rough or flawed edges of the tablet , Seriously affect the quality of sustained-release tablets, not only difficult to industrialized production, and the consistency of the product is also difficult to meet regulatory requirements.
专利文献CN104906064A涉及含普瑞巴林的胃漂浮缓释片，其认为遇水溶胀的药物存在诸多缺点，例如片剂边缘会造成胃肠道黏膜的损伤，且容易造成胃部的累积等。为此，该文献通过采用亲水性高分子材料和膨胀剂，使得片剂表面水化形成凝胶，从而使体积膨胀，继而漂浮于胃液上，延长胃内滞留时间。但是，该胃漂浮缓释片在胃内的漂浮需要较大量的胃液，并且对胃内容物密度和胃液的pH有较高要求，患者的个体差异会显著影响漂浮效果。Patent document CN104906064A relates to gastric floating sustained-release tablets containing pregabalin, which believes that there are many disadvantages in water-swellable drugs, such as damage to the gastrointestinal mucosa at the edge of the tablet, and easy accumulation in the stomach. For this reason, this document makes the surface of the tablet hydrated to form a gel by using a hydrophilic polymer material and a swelling agent, so that the volume expands, and then floats on the gastric juice to prolong the residence time in the stomach. However, the floating of the gastric floating sustained-release tablet in the stomach requires a large amount of gastric juice, and has high requirements on the density of gastric content and the pH of gastric juice, and the individual differences of patients will significantly affect the floating effect.
因此，亟需开发改善上述缺陷，更适于控制人体环境内药物释放，减少不同生理条件下的个体化差异的普瑞巴林的药物组合物。并且，该药物组合物的制备工艺适于工业化生产的规模和质量控制。Therefore, there is an urgent need to develop a pharmaceutical composition of pregabalin that improves the above defects, is more suitable for controlling drug release in the human environment, and reduces individual differences under different physiological conditions. Moreover, the preparation process of the pharmaceutical composition is suitable for the scale and quality control of industrial production.
发明内容Contents of the invention
为改善上述问题，本发明提供一种药物组合物，包含如下组分：In order to improve the above problems, the present invention provides a pharmaceutical composition comprising the following components:
Figure PCTCN2021105518-appb-000002
Figure PCTCN2021105518-appb-000002
其中，所述活性成分可采用普瑞巴林的任何药学上可接受形式，例如选自普瑞巴林、其药学上可接受的盐、配合物、溶剂化物或多晶型物中的一种、两种或更多种。Wherein, the active ingredient can be in any pharmaceutically acceptable form of pregabalin, for example, one or two selected from pregabalin, its pharmaceutically acceptable salt, complex, solvate or polymorph. species or more.
优选地，所述活性成分的含量以普瑞巴林计。Preferably, the content of the active ingredient is calculated as pregabalin.
根据本发明的实施方案，普瑞巴林药学上可接受的盐可以包括普瑞巴林与有机酸、无机酸、有机碱或无机碱形成的药学上可接受的盐，包括半盐。作为实例，药学上可接受的盐可以选自普瑞巴林的盐酸盐、氢溴酸盐、硫酸氢盐、钠盐、钾盐、镁盐等中的一种、 两种或更多种。According to an embodiment of the present invention, the pharmaceutically acceptable salt of pregabalin may include a pharmaceutically acceptable salt, including a half-salt, of pregabalin with an organic acid, an inorganic acid, an organic base or an inorganic base. As an example, the pharmaceutically acceptable salt may be one, two or more selected from pregabalin hydrochloride, hydrobromide, bisulfate, sodium salt, potassium salt, magnesium salt and the like.
根据本发明的实施方案，普瑞巴林的溶剂化物表示普瑞巴林和化学计量或非化学计量的一种、两种或更多种药学上可接受溶剂分子(例如醇类如乙醇、水或其混合物)的分子配合物。According to an embodiment of the present invention, a solvate of pregabalin means pregabalin and stoichiometric or non-stoichiometric amounts of one, two or more pharmaceutically acceptable solvent molecules (e.g. alcohols such as ethanol, water, or mixture) molecular complexes.
根据本发明的药物组合物中，所述至少一种选自普瑞巴林、其药学上可接受的盐或溶剂化物的活性成分的重量百分比含量可以为5～40％，例如5％、10％、15％、20％、25％、30％、35％或40％。In the pharmaceutical composition according to the present invention, the weight percentage content of the at least one active ingredient selected from pregabalin, its pharmaceutically acceptable salt or solvate can be 5-40%, such as 5%, 10% , 15%, 20%, 25%, 30%, 35% or 40%.
根据本发明的实施方案，所述骨架材料可以选自羟丙甲基纤维素、羟丙纤维素、聚丙烯酸树脂、卡波姆、聚醋酸乙烯酯聚维酮混合物、羟乙纤维素、乙基纤维素、聚乙烯醇、聚氧乙烯中的一种、两种或更多种。According to an embodiment of the present invention, the skeleton material may be selected from hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyacrylic acid resin, carbomer, polyvinyl acetate povidone mixture, hydroxyethyl cellulose, ethyl One, two or more of cellulose, polyvinyl alcohol, and polyoxyethylene.
根据本发明的药物组合物中，所述骨架材料的重量百分比含量可以为10～60％，例如10％、15％、20％、25％、30％、35％、40％、45％、50％、55％或60％。According to the pharmaceutical composition of the present invention, the weight percentage content of the skeleton material can be 10-60%, such as 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% %, 55% or 60%.
根据本发明的实施方案，所述膨胀剂可以选自交联聚乙烯吡咯烷酮(交联聚维酮)、交联羧甲基纤维素钠、羧甲基淀粉钠、低取代羟丙基纤维素、羧甲纤维素钙、羧甲纤维素、波拉克林钾中的一种、两种或更多种。According to an embodiment of the present invention, the expansion agent may be selected from cross-linked polyvinylpyrrolidone (crospovidone), cross-linked sodium carboxymethylcellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, One, two or more of carmellose calcium, carmellose, and polacrilin potassium.
根据本发明的药物组合物中，所述膨胀剂的重量百分比含量可以为1～25％，例如1％、2％、3％、4％、5％、10％、15％、20％或25％。According to the pharmaceutical composition of the present invention, the weight percentage content of the bulking agent can be 1-25%, such as 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20% or 25% %.
根据本发明的实施方案，所述填充剂可以选自乳糖、淀粉、甘露醇、微晶纤维素、磷酸氢钙中的一种、两种或更多种。According to an embodiment of the present invention, the filler may be selected from one, two or more of lactose, starch, mannitol, microcrystalline cellulose, and calcium hydrogen phosphate.
根据本发明的药物组合物中，所述填充剂的重量百分比含量可以为0～20％，例如0％或高于0％且不超过20％，如1％、2％、3％、4％、5％、10％、15％或20％。In the pharmaceutical composition according to the present invention, the weight percentage content of the filler can be 0-20%, such as 0% or higher than 0% and not more than 20%, such as 1%, 2%, 3%, 4%. , 5%, 10%, 15% or 20%.
根据本发明的实施方案，所述润滑剂可以选自滑石粉、硬脂酸镁、微粉硅胶中的一种、两种或更多种。According to an embodiment of the present invention, the lubricant may be selected from one, two or more of talcum powder, magnesium stearate, and micronized silica gel.
根据本发明的药物组合物中，所述润滑剂的重量百分比含量可以为0.5～5％，例如0.5％、1.0％、1.5％、2.0％、2.5％、3.0％、3.5％、4.0％、4.5％或5.0％。According to the pharmaceutical composition of the present invention, the weight percent content of the lubricant can be 0.5-5%, such as 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5% % or 5.0%.
根据本发明的实施方案，所述药物组合物可以为制剂(如片剂)，例如为普瑞巴林胃漂浮缓释制剂，优选普瑞巴林胃漂浮缓释片剂。According to an embodiment of the present invention, the pharmaceutical composition may be a preparation (such as a tablet), for example, a gastric-floating sustained-release preparation of pregabalin, preferably a pregabalin gastric-floating sustained-release tablet.
根据本发明的实施方案，所述药物组合物还可以包括包覆于上述组分外表面的包衣。According to an embodiment of the present invention, the pharmaceutical composition may further include a coating covering the outer surface of the above-mentioned components.
本发明还提供所述药物组合物的制备方法，包括将上述组分混合。优选地，所述制 备方法包括将活性成分、骨架材料、膨胀剂和填充剂混合均匀，然后加入润滑剂。The present invention also provides a preparation method of the pharmaceutical composition, comprising mixing the above components. Preferably, the preparation method includes uniformly mixing the active ingredient, skeleton material, expansion agent and filler, and then adding a lubricant.
优选地，所述制备方法还包括将上述组分混合后，将所得的混合物制备为制剂，例如通过压制步骤以及任选进行或不进行的包衣步骤，制备得到片剂。Preferably, the preparation method further includes mixing the above-mentioned components, and then preparing the obtained mixture into a preparation, for example, preparing a tablet through a compression step and an optional coating step.
根据本发明的药物组合物，其用于治疗或预防带状疱疹后神经痛。According to the pharmaceutical composition of the present invention, it is used for treating or preventing postherpetic neuralgia.
本发明还提供一种治疗或预防带状疱疹后神经痛的方法，包括将上述药物组合物施用于有需要的患者。The present invention also provides a method for treating or preventing postherpetic neuralgia, comprising administering the above pharmaceutical composition to a patient in need.
本发明还提供一种降低患者服药频率的方法，包括将上述药物组合物施用于有需要的患者，例如带状疱疹后神经痛的患者。优选地，患者服药的频率为每天至多服药一次。The present invention also provides a method for reducing the frequency of medication for patients, comprising administering the above pharmaceutical composition to patients in need, such as patients with postherpetic neuralgia. Preferably, the frequency of dosing by the patient is at most one dose per day.
本发明还提供一种改善患者服药依从性的方法，包括将上述药物组合物施用于有需要的患者，例如带状疱疹后神经痛的患者。The present invention also provides a method for improving patients' medication compliance, comprising administering the above pharmaceutical composition to patients in need, such as patients with postherpetic neuralgia.
本发明还提供将上述药物组合物用于制备药物的用途，其中所述药物用于治疗或预防带状疱疹后神经痛。The present invention also provides the use of the above-mentioned pharmaceutical composition for preparing a medicament, wherein the medicament is used for treating or preventing postherpetic neuralgia.
有益效果Beneficial effect
本发明药物组合物的药物释放性能优异。在体外溶出度试验中，第2小时释放25％～40％，第4小时释放40％～50％，第6小时释放55％～65％，第12小时释放80％以上，能够稳定释放药物，符合中国药典标准。另外，本发明药物组合物的包衣层进一步提高药品的稳定性，掩盖活性成分的苦味，且包衣层对片剂释放度无明显影响。The drug release performance of the pharmaceutical composition of the present invention is excellent. In the in vitro dissolution test, it releases 25%-40% in the 2nd hour, 40%-50% in the 4th hour, 55%-65% in the 6th hour, and more than 80% in the 12th hour. It can release the drug stably. Conform to Chinese Pharmacopoeia standard. In addition, the coating layer of the pharmaceutical composition of the present invention further improves the stability of the drug, masks the bitter taste of the active ingredient, and the coating layer has no obvious influence on the release rate of the tablet.
本发明的药物组合物可制备为日服一次的普瑞巴林胃漂浮型缓释片，并且该胃滞留片在胃中同时具有优异溶胀性和漂浮性，由此实现了将普瑞巴林延迟释放的特性，并能够有效延长普瑞巴林在胃和小肠上端的滞留时间，提高生物利用度，获得平稳的血药浓度，减少服用次数。本发明的药物组合物在患者服用后，能够在胃内水化膨胀至宽度大于13mm的尺寸。并且，缓释片接触胃液后，其密度低于胃液密度，从而迅速漂浮于胃液上部，且漂浮时间可持续高达超过24小时，达到胃内滞留的效果，提高生物利用度。同时，该缓释片具有较大的膨胀尺寸及较强的凝胶强度，从而减少不同生理条件下的个体化差异。The pharmaceutical composition of the present invention can be prepared as a gastric-floating sustained-release tablet of pregabalin once a day, and the gastric-retentive tablet has excellent swelling and floating properties in the stomach, thereby realizing the delayed release of pregabalin It can effectively prolong the residence time of pregabalin in the stomach and upper small intestine, improve bioavailability, obtain stable blood drug concentration, and reduce the frequency of administration. The pharmaceutical composition of the present invention can hydrate and expand in the stomach to a size with a width greater than 13 mm after being taken by a patient. Moreover, after the sustained-release tablet contacts the gastric juice, its density is lower than that of the gastric juice, so it quickly floats on the upper part of the gastric juice, and the floating time can last up to more than 24 hours, achieving the effect of gastric retention and improving bioavailability. At the same time, the sustained-release tablet has larger swelling size and stronger gel strength, thereby reducing individual differences under different physiological conditions.
此外，本发明药物组合物的辅料流动性好、抗粘性强，可在混合后直接压制得到普瑞巴林胃滞留缓释片，工艺简便易行，成本低廉，适于工业化生产。In addition, the excipients of the pharmaceutical composition of the present invention have good fluidity and strong anti-adhesive properties, and can be directly compressed to obtain pregabalin gastric retention sustained-release tablets after mixing. The process is simple and easy, the cost is low, and it is suitable for industrial production.
具体实施方式detailed description
本发明的实施方案将通过如下实施例得到进一步的解释和说明。但是，下文实施例不应被理解为对本发明专利范围的限制。应当指出的是，对于本领域的技术人员而言，在不脱离本发明构思的前提下，还可以做出若干变型和改进，这些变型和改进都属于本发明的保护范围。Embodiments of the present invention will be further explained and illustrated by the following examples. However, the following examples should not be construed as limiting the patent scope of the present invention. It should be noted that, for those skilled in the art, several modifications and improvements can be made without departing from the concept of the present invention, and these modifications and improvements all belong to the protection scope of the present invention.
除非另有说明，下文所使用的原料和试剂均可市售获得或通过已知的方法制备。其中：Unless otherwise stated, the starting materials and reagents used hereinafter are all commercially available or prepared by known methods. in:
普瑞巴林由奥锐特药业股份有限公司提供，纯度为99.2％；Pregabalin was provided by Orient Pharmaceutical Co., Ltd. with a purity of 99.2%;
交联聚维酮(PVPP)和聚醋酸乙烯酯聚维酮混合物(KSR)可得自BASF，其商品名分别为
Figure PCTCN2021105518-appb-000003
和
Figure PCTCN2021105518-appb-000004
其中
Figure PCTCN2021105518-appb-000005
标称为PVAc和PVP的80/19(w/w)混合物； Crospovidone (PVPP) and polyvinyl acetate povidone blend (KSR) are available from BASF under the tradenames
Figure PCTCN2021105518-appb-000003
and
Figure PCTCN2021105518-appb-000004
in
Figure PCTCN2021105518-appb-000005
Nominal 80/19 (w/w) mixture of PVAc and PVP;
羟乙基纤维素(HEC)可得自Ashland，其商品名为Natrosol TM，其分子量在约9×10 4至13×10 5(Mv)范围内，如HEC(HX Pharm)、HEC(M Pharm)； Hydroxyethyl cellulose (HEC) is available from Ashland under the tradename Natrosol ™ and has a molecular weight in the range of about 9×10 4 to 13×10 5 (Mv), such as HEC (HX Pharm), HEC (M Pharm );
乙基纤维素(EC)可得自Ashland，其商品名为Aqualon TM，其分子量在75000至215000(Mv)范围内，布氏粘度在8～105mPa.s范围内，如EC(T10 Pharm)； Ethylcellulose (EC) is available from Ashland under the trade name Aqualon ™ , with a molecular weight in the range of 75000 to 215000 (Mv) and a Brookfield viscosity in the range of 8 to 105 mPa.s, such as EC (T10 Pharm);
聚丙烯酸树脂是甲基丙烯酸二甲胺基乙酯、甲基丙烯酸、甲基丙烯酸酯按不同比例聚合得到的阳离子或阴离子型共聚物，可得自德国罗姆，商品名为
Figure PCTCN2021105518-appb-000006
Polyacrylic acid resin is a cationic or anionic copolymer obtained by polymerization of dimethylaminoethyl methacrylate, methacrylic acid, and methacrylate in different proportions. It can be obtained from Rohm, Germany, and its trade name is
Figure PCTCN2021105518-appb-000006
羟丙甲基纤维素可得自IFF公司，其商品名为METHOCEL TM，型号可选择K100LV、K4M和K100M； Hypromellose can be obtained from IFF Company, its trade name is METHOCEL TM , and the model can be selected from K100LV, K4M and K100M;
Figure PCTCN2021105518-appb-000007
SRP 80是基于亲水性聚合物聚乙烯醇(PVA)制备的功能性辅料，只含有单一成分-PVA 40-88*，不含有其它任何添加剂，可得自默克；
Figure PCTCN2021105518-appb-000007
SRP 80 is a functional excipient based on the hydrophilic polymer polyvinyl alcohol (PVA), containing only a single component - PVA 40-88*, without any other additives, available from Merck;
聚氧乙烯(PEO)可得自DOW公司，其商品名为POLYOX TM，其分子量在约9×10 5至7×10 6(Mv)范围内； Polyethylene oxide (PEO) is available from DOW Corporation under the trade name POLYOX ™ , and its molecular weight is in the range of about 9×10 5 to 7×10 6 (Mv);
卡波姆可得自RITA，其商品名为
Figure PCTCN2021105518-appb-000008
可得自Lubrizol，其商品名为
Figure PCTCN2021105518-appb-000009
其粘度范围可选择4000～39400cPs，如卡波姆971P； Carbomer is available from RITA under the trade name
Figure PCTCN2021105518-appb-000008
Available from Lubrizol under the tradename
Figure PCTCN2021105518-appb-000009
The viscosity range can be selected from 4000 to 39400cPs, such as Carbomer 971P;
羧甲纤维素钙(CMC-Ca)可得自Bolak公司，粒径范围可选择90～250目；Carmellose calcium (CMC-Ca) can be obtained from Bolak Company, and the particle size range can be selected from 90 to 250 mesh;
所述润滑剂可以选自滑石粉、硬脂酸镁、微粉硅胶中的一种、两种或更多种，其中硬脂酸镁可得自安徽山河；The lubricant can be selected from one, two or more of talcum powder, magnesium stearate, and micronized silica gel, wherein magnesium stearate can be obtained from Anhui Shanhe;
所述填充剂可以选自乳糖、淀粉、甘露醇、微晶纤维素、磷酸氢钙中的一种、两种或更多种。其中乳糖可得自美剂乐，微晶纤维素可得自瑞登梅尔(上海)纤维贸易有限公 司。The filler can be selected from one, two or more of lactose, starch, mannitol, microcrystalline cellulose, and calcium hydrogen phosphate. Among them, lactose can be obtained from MEGGLE, and microcrystalline cellulose can be obtained from Riddenmayer (Shanghai) Fiber Trading Co., Ltd.
本产品为薄膜包衣片，可得自卡乐康的
Figure PCTCN2021105518-appb-000010
系列。 This product is a film-coated tablet available from Colorcon as
Figure PCTCN2021105518-appb-000010
series.
实施例1至24：含有普瑞巴林的药物组合物Examples 1 to 24: Pharmaceutical compositions containing pregabalin
根据表1-5的组分和配比，将除硬脂酸镁以外的活性成分及辅料在三维运动混合机中混合20min，再加入硬脂酸镁继续混合5min，得到最终混合物。使用旋转压片机，22.0×10.9mm杏仁型冲压制成片剂，并进行包衣。其中，薄膜包衣预混剂厂家为卡乐康，型号为85F140030-CN。According to the components and proportions in Table 1-5, the active ingredients and auxiliary materials except magnesium stearate were mixed in a three-dimensional motion mixer for 20 minutes, and then magnesium stearate was added and mixed for 5 minutes to obtain the final mixture. Using a rotary tablet press, 22.0 × 10.9mm almond-shaped punched into tablets, and coated. Among them, the film coating premix manufacturer is Colorcon, and the model is 85F140030-CN.
除非另有说明，实施例1-24中各组分的数值代表其重量百分比(重量％)。Unless otherwise specified, the numerical values of each component in Examples 1-24 represent their weight percentages (wt%).
表1：实施例1-7Table 1: Examples 1-7
Figure PCTCN2021105518-appb-000011
Figure PCTCN2021105518-appb-000011
表2：实施例8-9Table 2: Examples 8-9
组分components 实施例8Example 8 实施例9Example 9
普瑞巴林Pregabalin 3030 3030
聚醋酸乙烯酯聚维酮混合物Polyvinyl acetate povidone blend 4040 4040
MCC 102MCC 102 5555 5555
CMC-CaCMC-Ca 1515 1515
PEO WSR N60KPEO WSR N60K 66  the
PEO WSR CoagulatPEO WSR Coagulat  the 66
卡波姆971PCarbomer 971P 33 33
硬脂酸镁Magnesium stearate 11 11
总计total 100.0100.0 100.0100.0
表3：实施例10-14Table 3: Examples 10-14
Figure PCTCN2021105518-appb-000012
Figure PCTCN2021105518-appb-000012
表4：实施例15-17Table 4: Examples 15-17
组分components 实施例15Example 15 实施例16Example 16 实施例17Example 17
普瑞巴林Pregabalin 3030 3030 3030
聚醋酸乙烯酯聚维酮混合物Polyvinyl acetate povidone blend 4040 4040 4040
CMC-CaCMC-Ca 1010 1717 2020
PEO WSR N60KPEO WSR N60K 1414  the 66
PEO WSR CoagulatPEO WSR Coagulat  the 88  the
卡波姆971PCarbomer 971P 55 44 33
硬脂酸镁Magnesium stearate 11 11 11
总计total 100.0100.0 100.0100.0 100.0100.0
表5：实施例18-24Table 5: Examples 18-24
Figure PCTCN2021105518-appb-000013
Figure PCTCN2021105518-appb-000013
实施例1-24的相关性能指标检测结果如下：The relevant performance index detection result of embodiment 1-24 is as follows:
Figure PCTCN2021105518-appb-000014
Figure PCTCN2021105518-appb-000014
其中：in:
1.物料流动性以卡尔指数的结果进行判断，评价方式如下：1. The fluidity of the material is judged by the result of the Carr index, and the evaluation method is as follows:
卡尔指数＝(振实密度-堆密度)/振实密度*100％Carr index = (tap density - bulk density) / tap density * 100%
卡尔指数Carr index 评价evaluate
5-15％5-15% 非常好very good
12-16％12-16% 好it is good
18-21％18-21% 一般generally
23-35％23-35% 差Difference
2.脆碎度检查方法见中国药典2020年版四部《0923片剂脆碎度检查法》。2. For the inspection method of friability, see the fourth part of the Chinese Pharmacopoeia 2020 Edition "0923 Tablet Friability Inspection Method".
比较例comparative example
本发明采用美国辉瑞制药有限公司生产的普瑞巴林缓释片(330mg)作为对照例。其中，该缓释片的组成为：含活性成分普瑞巴林330mg，其余组分包括聚醋酸乙烯酯聚维酮混合物，交联聚维酮，聚氧乙烯，卡波姆和硬脂酸镁。另比较例采用另了两个批次，分别计为比较例1和比较例2。The present invention adopts the pregabalin sustained-release tablet (330mg) produced by Pfizer Pharmaceutical Co., Ltd. of the United States as a control example. Wherein, the composition of the sustained-release tablet is: containing 330 mg of active ingredient pregabalin, and other components include polyvinyl acetate povidone mixture, cross-linked povidone, polyoxyethylene, carbomer and magnesium stearate. In another comparative example, two other batches were used, which are respectively counted as comparative example 1 and comparative example 2.
测试例1：体外释放度试验Test Example 1: In Vitro Release Test
根据中国药典2015版四部附录溶出度与释放度测定法第二法(桨法)，采用900mL的0.06mol·L -1HCl溶液(pH＝1.2)为释放介质，转速为50rpm，温度为37℃，依法操作，于0.5、1、2、4、6、9、12、16、20、24h取样品1.5mL，以HPLC(检测波长＝205nm)进行检测，并计算释放度。 According to the second method (paddle method) of the four appendices of the Chinese Pharmacopoeia 2015 edition, 900mL of 0.06mol L -1 HCl solution (pH=1.2) was used as the release medium, the rotation speed was 50rpm, and the temperature was 37°C. , operate according to the law, take 1.5mL samples at 0.5, 1, 2, 4, 6, 9, 12, 16, 20, 24h, detect with HPLC (detection wavelength = 205nm), and calculate the release degree.
如表6-8所示，根据本发明制备的普瑞巴林制剂显示出优异的缓释溶出模式。通过调节缓释制剂的各组分及比例，制得的普瑞巴林缓释制剂1小时基本无突释效应，8小时溶出量为50％至70％，16小时的释药量超过80％。比较例中药片1小时累积溶出率约20％，显示出一定的突释效应，而根据本发明制备的片剂显著削弱了这种突释效应，使普瑞巴林以更加平缓的方式释药，增加了用药的安全性。As shown in Tables 6-8, the pregabalin formulations prepared according to the present invention exhibit excellent sustained-release dissolution patterns. By adjusting the components and proportions of the sustained-release preparation, the prepared pregabalin sustained-release preparation has basically no burst release effect in 1 hour, the dissolution rate is 50% to 70% in 8 hours, and the release rate exceeds 80% in 16 hours. The cumulative dissolution rate of the tablets in the comparative example was about 20% in 1 hour, showing a certain burst release effect, while the tablet prepared according to the present invention significantly weakened this burst release effect, making pregabalin release in a more gradual manner, Increased the safety of medication.
表6：实施例1～8与比较例的释放度数据对比Table 6: Comparison of release data between Examples 1-8 and Comparative Examples
Figure PCTCN2021105518-appb-000015
Figure PCTCN2021105518-appb-000015
表7：实施例9～16与比较例的释放度数据对比Table 7: Comparison of release data between Examples 9-16 and Comparative Examples
Figure PCTCN2021105518-appb-000016
Figure PCTCN2021105518-appb-000016
表8：实施例17～24与比较例的释放度数据对比Table 8: Comparison of release data between Examples 17-24 and Comparative Examples
Figure PCTCN2021105518-appb-000017
Figure PCTCN2021105518-appb-000017
Figure PCTCN2021105518-appb-000018
Figure PCTCN2021105518-appb-000018
测试例2：漂浮性能测定Test Example 2: Determination of floating performance
根据中国药典2015版四部附录溶出度与释放度测定法第二法(桨法)，采用900mL0.06mol·L -1HCl溶液(pH＝1.2)为释放介质，转速为50rpm，温度为37℃，对上述实施例中制备的药片进行溶出试验。将胃漂浮缓释片投入介质中，开始计时，从开始计时到胃漂浮缓释片从溶出杯底漂浮到液面上的时间为起漂时间，胃漂浮缓释片在液面上持续漂浮的时间为持漂时间，数据如表9～11所示。 According to the second method (paddle method) of the four appendices of the Chinese Pharmacopoeia 2015 edition, 900mL0.06mol L -1 HCl solution (pH=1.2) was used as the release medium, the rotating speed was 50rpm, and the temperature was 37°C. Dissolution tests were performed on the tablets prepared in the above examples. Put the gastric floating sustained-release tablet into the medium, and start timing. The time from the start of timing to the gastric floating sustained-release tablet floating from the bottom of the dissolution vessel to the liquid surface is the floating time, and the gastric floating sustained-release tablet continues to float on the liquid surface. The time is the drift time, and the data are shown in Tables 9-11.
通过表9～11可知，本发明的实施例1-24中的药品在溶出过程中均能立即起漂，显著降低了了药片与胃内食物接触的几率。并且，实施例2、4、7、9-12、14-19、21在介质表面漂浮时间(持漂时间)超过24小时，提高药片在胃中的滞留时间，而其他实施例也至少达到了与比较例相当的滞留时间。因此，本发明实施例1-24的起漂和持漂的综合性能显著优于比较例。It can be known from Tables 9-11 that the medicines in Examples 1-24 of the present invention can float immediately during the dissolution process, which significantly reduces the probability of contact between the tablet and the food in the stomach. And, embodiment 2, 4, 7, 9-12, 14-19, 21 surpass 24 hours on medium surface floating time (sustain floating time), improve the residence time of tablet in stomach, and other embodiments have also reached at least The residence time is equivalent to that of the comparative example. Therefore, the comprehensive performances of bleach initiation and bleach retention in Examples 1-24 of the present invention are significantly better than those of Comparative Examples.
表9：实施例1～8与比较例的漂浮性能对比Table 9: Comparison of floating performance between Examples 1-8 and Comparative Example
Figure PCTCN2021105518-appb-000019
Figure PCTCN2021105518-appb-000019
表10：实施例9～16与比较例的漂浮性能对比Table 10: Comparison of the floating performance of Examples 9-16 and Comparative Examples
Figure PCTCN2021105518-appb-000020
Figure PCTCN2021105518-appb-000020
表11：实施例17～24与比较例的漂浮性能对比Table 11: Comparison of the floating performance of Examples 17-24 and Comparative Examples
Figure PCTCN2021105518-appb-000021
Figure PCTCN2021105518-appb-000021
测试例3：溶胀尺寸的测量Test Example 3: Measurement of Swelled Size
根据中国药典2015版四部附录溶出度与释放度测定法第二法(桨法)，采用900mL0.06mol·L -1HCl溶液(pH＝1.2)为释放介质，转速为50rpm，温度为37℃，对上述实施例中制备的药片进行溶出试验。分别测量溶出24h后的药片尺寸(测量结果为三个药片的平均值)。如表12所示，根据本发明制备的药片的尺寸(宽)增大到13mm以上，这种尺寸可允许胃 滞留。 According to the second method (paddle method) of the four appendices of the Chinese Pharmacopoeia 2015 edition, 900mL0.06mol L -1 HCl solution (pH=1.2) was used as the release medium, the rotating speed was 50rpm, and the temperature was 37°C. Dissolution tests were performed on the tablets prepared in the above examples. The tablet size after dissolution for 24 hours was measured respectively (the measurement result is the average value of three tablets). As shown in Table 12, the size (width) of the tablets prepared according to the present invention increased to more than 13 mm, which size allowed gastric retention.
通过表12的测量结果可知，本发明实施例药品均具有较强的溶胀性，使得药品进入胃中，快速膨胀，提高药片在胃中的滞留时间。From the measurement results in Table 12, it can be known that the medicines in the examples of the present invention have strong swelling properties, so that the medicines enter the stomach, expand rapidly, and increase the residence time of the tablets in the stomach.
表12：实施例与比较例的溶出片尺寸数据对比Table 12: Comparison of the size data of the dissolution tablet of the embodiment and the comparative example
Figure PCTCN2021105518-appb-000022
Figure PCTCN2021105518-appb-000022
测试例4：刚性Test Example 4: Rigidity
根据中国药典2015版四部附录溶出度与释放度测定法第二法(桨法)，采用900mL0.06mol·L -1的HCl溶液(pH＝1.2)为释放介质，转速为50rpm，温度为37℃，对上述实施例中制备的药片进行溶出试验。24小时后从溶出介质中取出药品试样，并在一下设定条件 下使用Rapid TA +质构仪测定其刚性：10kg负载单位；36mm柱形探头；6.0g触发力；1.0毫米/秒测试速度；下压样品片高度的30％。结果显示于表13中。 According to the second method (paddle method) of the four appendices of the Chinese Pharmacopoeia 2015 edition, 900mL of 0.06mol L -1 HCl solution (pH=1.2) was used as the release medium, the rotation speed was 50rpm, and the temperature was 37°C , Dissolution test was carried out on the tablets prepared in the above examples. After 24 hours, take out the drug sample from the dissolution medium, and use the Rapid TA + texture analyzer to measure its rigidity under the following setting conditions: 10kg load unit; 36mm cylindrical probe; 6.0g trigger force; 1.0 mm/s test speed ; Press down to 30% of the height of the sample piece. The results are shown in Table 13.
如表13所示，相比于比较例中的药片，本发明制备的药片(实施例13和实施例15)溶胀24h后刚性更为优良，显示出良好的胃滞留特性，进而有效控制药物释放，提高生物利用度。As shown in Table 13, compared with the tablets in Comparative Examples, the tablets prepared by the present invention (Example 13 and Example 15) have better rigidity after swelling for 24 hours, showing good gastric retention characteristics, and effectively controlling drug release. , improve bioavailability.
表13：实施例与比较例的溶出片刚性数据对比Table 13: Comparison of the rigidity data of the dissolution tablet of the embodiment and the comparative example
实施例Example 硬度(gf)Hardness (gf) 样品高度Sample height
22 190.000190.000 15.34015.340
55 165.250165.250 12.45312.453
88 134.900134.900 12.44512.445
1010 192.150192.150 12.93012.930
1313 192.150192.150 12.52812.528
1515 225.150225.150 12.75512.755
比较例2Comparative example 2 148.700148.700 13.8113.81

Claims (10)

  1. 一种药物组合物，包含如下组分：A pharmaceutical composition comprising the following components:
    Figure PCTCN2021105518-appb-100001
    Figure PCTCN2021105518-appb-100001
    其中，所述活性成分可采用普瑞巴林的任何药学上可接受形式，例如选自普瑞巴林、其药学上可接受的盐、配合物、溶剂化物或多晶型物中的一种、两种或更多种；Wherein, the active ingredient can be in any pharmaceutically acceptable form of pregabalin, for example, one or two selected from pregabalin, its pharmaceutically acceptable salt, complex, solvate or polymorph. one or more kinds;
    所述骨架材料选自羟丙甲基纤维素、羟丙纤维素、聚丙烯酸树脂、卡波姆、聚醋酸乙烯酯聚维酮混合物、羟乙纤维素、乙基纤维素、聚乙烯醇、聚氧乙烯中的一种、两种或更多种；The skeleton material is selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyacrylic acid resin, carbomer, polyvinyl acetate povidone mixture, hydroxyethyl cellulose, ethyl cellulose, polyvinyl alcohol, poly One, two or more of oxyethylene;
    所述膨胀剂选自交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、低取代羟丙基纤维素、羧甲纤维素钙、羧甲纤维素、波拉克林钾中的一种、两种或更多种。The expansion agent is selected from cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, carmellose calcium, carmellose, polacrilin potassium one, two or more of them.
  2. 如权利要求1所述的药物组合物，其中：The pharmaceutical composition as claimed in claim 1, wherein:
    普瑞巴林药学上可接受的盐选自普瑞巴林与有机酸、无机酸、有机碱或无机碱形成的药学上可接受的盐，包括半盐；例如，所述药学上可接受的盐可以选自普瑞巴林的盐酸盐、氢溴酸盐、硫酸氢盐、钠盐、钾盐、镁盐等中的一种、两种或更多种；The pharmaceutically acceptable salt of pregabalin is selected from the pharmaceutically acceptable salts formed by pregabalin and organic acid, inorganic acid, organic base or inorganic base, including half salts; for example, the pharmaceutically acceptable salt can be One, two or more selected from pregabalin hydrochloride, hydrobromide, hydrogen sulfate, sodium salt, potassium salt, magnesium salt, etc.;
    普瑞巴林的溶剂化物表示普瑞巴林和化学计量或非化学计量的一种、两种或更多种药学上可接受溶剂分子(例如醇类如乙醇、水或其混合物)的分子配合物。Solvates of pregabalin mean molecular complexes of pregabalin and stoichiometric or non-stoichiometric amounts of one, two or more molecules of a pharmaceutically acceptable solvent such as alcohols such as ethanol, water, or mixtures thereof.
  3. 如权利要求1或2所述的药物组合物，其中：The pharmaceutical composition as claimed in claim 1 or 2, wherein:
    所述填充剂可以选自乳糖、淀粉、甘露醇、微晶纤维素、磷酸氢钙中的一种、两种或更多种；The filler can be selected from one, two or more of lactose, starch, mannitol, microcrystalline cellulose, and calcium hydrogen phosphate;
    所述润滑剂可以选自滑石粉、硬脂酸镁、微粉硅胶中的一种、两种或更多种。The lubricant may be selected from one, two or more of talcum powder, magnesium stearate, and micronized silica gel.
  4. 如权利要求1-3任一项所述的药物组合物，其中所述药物组合物为制剂(如片剂)，例如为普瑞巴林胃漂浮缓释制剂，优选普瑞巴林胃漂浮缓释片剂。The pharmaceutical composition according to any one of claims 1-3, wherein the pharmaceutical composition is a preparation (such as a tablet), such as a pregabalin gastric floating sustained-release preparation, preferably a pregabalin gastric floating sustained-release tablet agent.
  5. 如权利要求1-4任一项所述的药物组合物，其中所述药物组合物还可以包括包覆于上述组分外表面的包衣。The pharmaceutical composition according to any one of claims 1-4, wherein the pharmaceutical composition may further comprise a coating coated on the outer surface of the above-mentioned components.
  6. 如权利要求1-5任一项所述的药物组合物的制备方法，包括将所述组分混合；The preparation method of the pharmaceutical composition according to any one of claims 1-5, comprising mixing the components;
    例如，所述制备方法包括将活性成分、骨架材料、膨胀剂和填充剂混合均匀，然后加入润滑剂；For example, the preparation method includes uniformly mixing the active ingredient, skeleton material, expansion agent and filler, and then adding a lubricant;
    优选地，所述制备方法还包括将上述组分混合后，将所得的混合物制备为制剂。Preferably, the preparation method further includes mixing the above-mentioned components, and then preparing the obtained mixture into a preparation.
  7. 一种治疗或预防带状疱疹后神经痛的方法，包括将如权利要求1-5任一项所述的药物组合物施用于有需要的患者。A method for treating or preventing postherpetic neuralgia, comprising administering the pharmaceutical composition according to any one of claims 1-5 to a patient in need.
  8. 一种降低患者服药频率的方法，包括将如权利要求1-5任一项所述的药物组合物施用于有需要的患者，例如带状疱疹后神经痛的患者；A method for reducing the frequency of medication for patients, comprising administering the pharmaceutical composition according to any one of claims 1-5 to patients in need, such as patients with postherpetic neuralgia;
    优选地，患者服药的频率为每天至多服药一次。Preferably, the frequency of dosing by the patient is at most one dose per day.
  9. 一种改善患者服药依从性的方法，包括将如权利要求1-5任一项所述的药物组合物施用于有需要的患者，例如带状疱疹后神经痛的患者。A method for improving patients' medication compliance, comprising administering the pharmaceutical composition according to any one of claims 1-5 to patients in need, such as patients with postherpetic neuralgia.
  10. 如权利要求1-5任一项所述的药物组合物用于制备药物的用途，其中所述药物用于治疗或预防带状疱疹后神经痛。Use of the pharmaceutical composition according to any one of claims 1-5 for preparing a medicament, wherein the medicament is used for treating or preventing postherpetic neuralgia.
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