WO2022179635A1 - β-NICOTINAMIDE MONONUCLEOTIDE FREEZE-DRIED ORAL PREPARATION - Google Patents

β-NICOTINAMIDE MONONUCLEOTIDE FREEZE-DRIED ORAL PREPARATION Download PDF

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Publication number
WO2022179635A1
WO2022179635A1 PCT/CN2022/078131 CN2022078131W WO2022179635A1 WO 2022179635 A1 WO2022179635 A1 WO 2022179635A1 CN 2022078131 W CN2022078131 W CN 2022078131W WO 2022179635 A1 WO2022179635 A1 WO 2022179635A1
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WO
WIPO (PCT)
Prior art keywords
freeze
nicotinamide mononucleotide
oral preparation
gelatin
dried
Prior art date
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PCT/CN2022/078131
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French (fr)
Chinese (zh)
Inventor
张严源
陈剑
洪朝阳
李鹏飞
梁凯
吴龙昊
梁莹莹
肖立
Original Assignee
北京兴源联合医药科技有限公司
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Publication date
Priority claimed from CN202110222605.5A external-priority patent/CN114983950A/en
Priority claimed from CN202110222616.3A external-priority patent/CN115054580A/en
Application filed by 北京兴源联合医药科技有限公司 filed Critical 北京兴源联合医药科技有限公司
Publication of WO2022179635A1 publication Critical patent/WO2022179635A1/en

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Classifications

    • 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, pantothenic acid
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • 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
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present application relates to the field of freeze-dried preparations in the field of biomedicine, in particular to a freeze-dried oral preparation of beta-nicotinamide mononucleotide.
  • Beta-nicotinamide mononucleotide referred to as NMN
  • NMN has the effect of delaying, improving and preventing aging.
  • Orally disintegrating tablets containing ⁇ -nicotinamide mononucleotide-containing medicines or health care products can improve the problem of poor medication compliance of patients with difficulty in taking medicines, especially mentally ill patients with vomiting and Vietnamese medicine problems, and Children who are prone to refuse medicine and choke on medicine.
  • the freeze-dried orally disintegrating tablets have the characteristics of fast disintegration speed, less amount of auxiliary materials, good taste, and are suitable for the preparation of heat-sensitive drugs.
  • a lyophilized oral preparation of ⁇ -nicotinamide mononucleotide includes a pharmaceutical active ingredient and a binder; the pharmaceutical active ingredient is ⁇ -nicotinamide mononucleotide or a pharmaceutically acceptable salt thereof, the binder is gelatin, and the frozen
  • the dry oral formulation does not contain a lyophilized proppant.
  • the gelatin is selected from one or more of cowhide gelatin, fish skin gelatin, bovine bone glue, pig bone glue, and fish bone glue.
  • the lyophilized oral formulation further comprises a flavoring agent.
  • the flavoring agent is selected from one or more of aspartame, sodium cyclamate, sodium saccharin, and sucralose.
  • the lyophilized proppant is selected from one or more of sugars, sugar alcohols, amino acids, and povidone.
  • the lyophilized proppant is selected from one or more of mannitol, dextran, lactose, trehalose, povidone, sorbitol, amino acid, and pullulan.
  • the gelatin comprises 2-8.5% of the total weight of the lyophilized oral formulation.
  • the gelatin comprises 3.4-7.4% of the total weight of the lyophilized oral formulation.
  • the lyophilized oral formulation contains 60-200 mg of the active pharmaceutical ingredient in a unit dose.
  • the lyophilized oral formulation is an orally disintegrating tablet.
  • pharmaceutically acceptable salt refers to the form of a pharmaceutically active ingredient, including pharmaceutically acceptable salts of organic acids and bases or inorganic acids and bases.
  • unit dose refers to a single dose which can be administered to a subject and which is easy to handle and package.
  • a unit dose can be a single tablet, pill, capsule, lozenge, suppository, cachet, drops, ampoules, and the like.
  • the term “strength” refers to the amount of active pharmaceutical ingredient in a unit dose of a pharmaceutical product.
  • the pharmaceutical product may be a tablet, and the specification may refer to the content of the pharmaceutically active ingredient in a single tablet of the pharmaceutical product.
  • a 60 mg strength tablet may be a single tablet containing 60 mg of the active pharmaceutical ingredient.
  • the content of the active pharmaceutical ingredient is calculated as the pharmaceutical compound. If the active pharmaceutical ingredient is a pharmaceutically acceptable salt of the pharmaceutical compound, the conversion shall be carried out according to the pharmaceutical compound.
  • large unit dose refers to a unit dose of a pharmaceutical product containing more than 60 mg of the active pharmaceutical ingredient.
  • water-soluble pharmaceutical active ingredient refers to a pharmaceutical active ingredient whose solubility in water is greater than 1 g/30 mL at room temperature or room temperature.
  • the water-soluble pharmaceutical active ingredient includes oseltamivir, pregabalin, beta-nicotinamide mononucleotide, and pharmaceutically acceptable salts thereof.
  • the term "poorly water-soluble pharmaceutical active ingredient” refers to a pharmaceutical active ingredient that is insoluble or slightly soluble in water at normal or room temperature.
  • the poorly water-soluble pharmaceutically active ingredients include phosphatidylserine and pharmaceutically acceptable salts thereof.
  • This specification provides a lyophilized oral preparation of ⁇ -nicotinamide mononucleotide, which is a large-scale unit dose lyophilized oral preparation of ⁇ -nicotinamide mononucleotide, and meets the requirements of appearance, disintegration , dissolution, product stability and other quality index requirements.
  • the freeze-dried oral preparation of this embodiment includes a pharmaceutical active ingredient and a binder, and the pharmaceutical active ingredient is ⁇ -nicotinamide mononucleotide, or a pharmaceutically acceptable salt thereof.
  • the lyophilized oral formulation includes, but is not limited to, oral formulations in the form of tablets, pills, granules, and the like.
  • the lyophilized oral formulation is a lyophilized orally disintegrating tablet.
  • the binder can be gelatin, and the lyophilized oral formulation does not contain a lyophilized proppant.
  • gelatins that can be used as binders include, but are not limited to, cowhide gelatin, fish skin gelatin, pigskin gelatin, horse skin gelatin, donkey skin gelatin, beef bone glue, fish bone glue, pig bone glue, horse bone glue, donkey bone glue Bone glue etc.
  • the gelatin may be selected from one or more of cowhide gelatin, fish skin gelatin, pigskin gelatin, bovine bone glue, fish bone glue, and pig bone glue.
  • gelatin may comprise 2-8.5% of the total weight of the lyophilized oral formulation.
  • gelatin may comprise about 2%, 2.2%, 2.4%, 2.6%, 2.8%, 3%, 3.2%, 3.4%, 3.6%, 3.8%, 4% by weight of the total lyophilized oral formulation %, 4.2%, 4.4%, 4.6%, 4.8%, 5%, 5.2%, 5.4%, 5.6%, 5.8%, 6%, 6.2%, 6.4%, 6.6%, 6.8%, 7%, 7.2%, 7.4%, 7.6%, 7.8%, 8%, 8.2%, 8.4% or 8.5%. It also includes any range characterized by a combination of the above-mentioned end values, which will not be repeated here.
  • gelatin may comprise 3.4-7.4% of the total weight of the lyophilized oral formulation.
  • a unit dose of the lyophilized oral formulation may contain about 2-9.25 mg of gelatin.
  • the gelatin content of the lyophilized oral formulation in a unit dose may be about 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg mg, 8 mg, 8.5 mg, 9 mg or 9.25 mg. It also includes any range characterized by a combination of the above-mentioned end values, which will not be repeated here.
  • the lyophilized oral formulation does not include a lyophilized proppant selected from one or more of sugars, sugar alcohols, amino acids, and povidone (PVP).
  • excluded lyophilized proppants include, but are not limited to, glucose, sucrose, fructose, xylose, lactose, galactose, maltose, isomalt, mannose, sorbose, trehalose, raffinose, Lulan, dextran, xylitol, sorbitol, isosorbide, mannitol, erythritol, maltitol, isomalt, lactitol, glycine, alanine, valine, proline, serine , cysteine, asparagine, glutamine, threonine, lysine, arginine, histidine, PVP k30, etc.
  • the excluded lyophilized proppants include, but are not limited to, glucose
  • a unit dose of the lyophilized oral formulation may contain about 60-200 mg of the active pharmaceutical ingredient. In some embodiments, a unit dose of the lyophilized oral formulation may contain about 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg of the active pharmaceutical ingredient , 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg or 200mg.
  • the lyophilized oral formulation may contain about 100 mg of beta-nicotinamide mononucleotide in a unit dose.
  • the freeze-dried oral formulation of this embodiment also contains one or more of flavoring agents, flavoring agents, coloring agents and preservatives as required.
  • flavoring agents include sweetening agents.
  • This embodiment includes sweeteners other than sugars and sugar alcohols, which can be used as flavoring agents to improve or shield the bad smell and taste of drugs and can also be used as freeze-dried proppants.
  • the flavoring agent of this embodiment can be a non-sugar sweetener, including but not limited to aspartame, sodium cyclamate, sodium saccharin, sucralose, aspartame, acesulfame potassium, alitame, neotame, Stevioside, thaumatin, mogrosin, thomastin, etc.
  • the flavoring agent is selected from one or more of aspartame, sodium cyclamate, sodium saccharin, and sucralose.
  • the content of the flavoring agent in a unit dose of the lyophilized oral formulation may be about 0.05-0.5 mg. In some embodiments, the content of the flavoring agent in the unit dose of the lyophilized oral formulation may be about 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg or 0.5mg. It also includes any range characterized by a combination of the above-mentioned end values, which will not be repeated here.
  • test materials in the following examples are conventional methods unless otherwise specified.
  • the test materials used in the following examples were purchased from conventional biochemical reagent companies unless otherwise specified.
  • Appearance evaluation Take the orally disintegrating tablet upwards from the bottom of the blister with your fingers, and observe the appearance, smoothness, depression, cracks, sticking to the bottom, shrinkage, etc. with the naked eye.
  • the orally disintegrating tablet meltability test was performed to simulate its release in the oral cavity according to USP standards. Put the sample into 2 mL of water at 37°C, observe the phenomenon still, and measure the time for complete disintegration. Measurements were repeated in 6 independent experiments and results are given as mean values in seconds.
  • step 2) according to the formula table of different embodiments, take by weighing other components of formula quantity, add in step 1) gained mixed solution, stir until completely dissolved; add water to 100mL, stir evenly.
  • step 3 After filtration and sterilization, the mixed solution obtained in step 2) is added to the blister under aseptic conditions.
  • freeze-drying to obtain the finished product of the orally disintegrating tablet.
  • the conditions for freeze-drying described above are shown in the tables of the various examples.
  • Example 1 Large-scale ⁇ -nicotinamide mononucleotide orally disintegrating tablet
  • Orally disintegrating tablets sample 1 to sample 11 were prepared by the aforementioned preparation method of lyophilized oral preparation, and the pharmaceutical active ingredient of sample 1 to sample 11 was ⁇ -nicotinamide mononucleotide.
  • samples 1 to 3 are prepared under the conditions of freeze-drying parameters 1, 2, and 3 as shown in Table 1.1, respectively; and samples 4 to 7 are the formulas shown in Table 1.1.
  • 2 to formula 5 were prepared under the conditions of freeze-drying parameter 4 shown in Table 5.3; similarly, samples 8 to 11 were the freeze-dried formulas 2 to 5 shown in Table 1.1, respectively, as shown in Table 5.3 prepared under the conditions of parameter 5.
  • a total of 200 orally disintegrating tablets from Sample 1 to Sample 11 were prepared, with a specification of 100 mg/tablet.
  • Sample 4 Sample 5
  • Sample 6 Sample 7
  • Sample 7 are large-format ⁇ -nicotinamide mononucleotide orally disintegrating tablets containing only flavoring agent aspartame and non-gelatin gum-based binder.
  • the bottom of sample 4 to sample 7 has different degrees of sticking to the bottom, the bottom shrinks, and the molding effect is not good.
  • Sample 8, sample 9, sample 10 and sample 11 are large-sized ⁇ -nicotinamide mononucleotide orally disintegrating tablets prepared based on the formulations of samples 4 to 7 after optimization of freeze-drying parameters. Samples 8 to 11 still have problems such as sticking to the bottom and shrinking of the bottom to different degrees, and optimizing the freeze-drying parameters did not significantly improve the molding effect of the samples.
  • Samples 1 to 3 are large-scale ⁇ -nicotinamide mononucleotide orally disintegrating tablets containing only aspartame as a flavoring agent and gelatin as a binder. Samples 1 to 3 all have a complete sheet shape, a smooth surface, no cracks or sticking to the bottom, and the molding state is good.
  • Sample serial number Molded appearance 1 The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom. 2
  • the sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom.
  • 3 The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom.
  • Example 2 Large-scale ⁇ -nicotinamide mononucleotide orally disintegrating tablet
  • Orally disintegrating tablet samples 12 to 14 were prepared by the aforementioned preparation method of lyophilized oral preparation, and the active pharmaceutical ingredient of samples 12 to 14 was ⁇ -nicotinamide mononucleotide.
  • sample 12 is prepared by formula 1 shown in Table 2.1 under the freeze-drying conditions shown in table 2.2; similarly, sample 13 and sample 14 are formula 2 and formula 3 shown in Table 2.1 respectively in Corresponding to the freeze-drying conditions shown in Table 2.2.
  • a total of 200 orally disintegrating tablets from Sample 12 to Sample 14 were prepared, with a specification of 100 mg/tablet.
  • Bovine bone gelatin was purchased from Rousselot (Da'an) Gelatin Co., Ltd.; fish skin gelatin was purchased from Guangzhou Shengtong Trading Co., Ltd.; fish bone gelatin was purchased from Jiangxi Fumeitai Biotechnology Co., Ltd.
  • Sample serial number Molded appearance 12 The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom. 13 The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom. 14 The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom.
  • Samples 12 to 14 are large-format ⁇ -nicotinamide mononucleotide orally disintegrating tablets containing aspartame and gelatin from different sources.
  • the above physical and chemical properties test results show that samples 12 to 14 are all in a complete sheet shape, with smooth surfaces, no cracks and sticking to the bottom, and the molding state is good.
  • the large-sized ⁇ -nicotinamide mononucleotide orally disintegrating tablets of samples 12 to 14 containing gelatin from different sources were all excellent in the molding effect.
  • Example 3 Large-scale ⁇ -nicotinamide mononucleotide orally disintegrating tablet
  • Orally disintegrating tablet samples 15 to 18 were prepared by the aforementioned preparation method of lyophilized oral preparation, and the active pharmaceutical ingredient of samples 15 to 18 was ⁇ -nicotinamide mononucleotide.
  • sample 15 is prepared by formula 1 shown in Table 3.1 under the freeze-drying conditions shown in table 2.2 of Example 2; similarly, sample 16, sample 17 and sample 18 are the formulas shown in table 3.1 2.
  • Formula 3 and Formula 4 were prepared under the freeze-drying conditions shown in Table 2.2 of Example 2, respectively.
  • a total of 200 orally disintegrating tablets from Sample 15 to Sample 18 were prepared, with a specification of 100 mg/tablet.
  • Gelatin 150LB8 and gelatin 180LB8 were purchased from Rousselot (Da'an) Gelatin Co., Ltd.; gelatin for capsules was purchased from Ningxia Xinhaoyuan Biotechnology Co., Ltd.; bovine hydrolyzed gelatin was purchased from Shanghai Linchen Pharmaceutical Technology Co., Ltd.
  • Sample serial number Molded appearance 15 The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom. 16 The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom. 17 The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom. 18 The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom.
  • Samples 15 to 18 are large-scale ⁇ -nicotinamide mononucleotide orally disintegrating tablets containing aspartame and different types of bovine bone gelatin.
  • the above-mentioned physical and chemical properties testing results show that the samples 15 to 18 are all sheet-shaped and complete, the surface is smooth, and there is no crack or sticking to the bottom, and the molding state is good.
  • the large-sized ⁇ -nicotinamide mononucleotide orally disintegrating tablets of samples 15 to 18 containing different types of bovine bone gelatin have good molding effect, good physical and chemical properties, and all quality indicators can meet the requirements.
  • Example 4 Large-scale ⁇ -nicotinamide mononucleotide orally disintegrating tablet
  • Orally disintegrating tablet samples 19 to 21 were prepared by the aforementioned preparation method of lyophilized oral preparation, and the active pharmaceutical ingredient of samples 19 to 21 was ⁇ -nicotinamide mononucleotide.
  • sample 19 is prepared by formula 1 shown in Table 4.1 under the freeze-drying conditions shown in table 1.2; similarly, sample 20 and sample 21 are formula 2 and formula 3 shown in table 4.1 in the corresponding prepared under the freeze-drying conditions shown in Table 1.2.
  • a total of 200 orally disintegrating tablets from Sample 19 to Sample 21 were prepared, with a specification of 100 mg/tablet.
  • Sample 20 is ⁇ -nicotinamide mononucleotide orally disintegrating tablet containing gelatin, lyophilized proppant mannitol and flavoring agent
  • sample 21 is ⁇ -nicotinamide mononucleate containing only lyophilized proppant mannitol and flavoring agent Glycosides orally disintegrating tablets. It can be seen from the test results of physical and chemical properties that the molding effect of sample 20 and sample 21 is not good, the disintegration time is relatively long, and neither can meet the corresponding quality index requirements.
  • Sample 19 is an orally disintegrating tablet containing only gelatin and aspartame. Compared with sample 20 and sample 21, the large-sized ⁇ -nicotinamide mononucleotide orally disintegrating tablet of sample 19 contains less excipients and has better molding effect and shorter disintegration time.
  • Example 5 Large-scale ⁇ -nicotinamide mononucleotide orally disintegrating tablet
  • Orally disintegrating tablet samples 22 to 29 were prepared by the aforementioned preparation method of lyophilized oral preparation, and the active pharmaceutical ingredient of samples 22 to 29 was ⁇ -nicotinamide mononucleotide.
  • sample 22 is prepared from formula 1 shown in Table 5.1 under freeze-drying conditions corresponding to those shown in table 5.2; similarly, samples 23 to 29 are formula 2 to formula 8 shown in table 5.1 respectively in Corresponding to the freeze-drying conditions shown in Table 5.2.
  • a total of 200 orally disintegrating tablets from Sample 22 to Sample 29 were prepared, with a specification of 100 mg/tablet.
  • Sample serial number Molded appearance disintegration time twenty two Slightly loose, not dense, easy to break when taken; no cracks, no sticking to the bottom / twenty three
  • the sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom. 6s twenty four The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom. 7s 25 The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom. 8s 26 The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom. 9s 27
  • the sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom.
  • 10s 28 The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom. 10s 29 The sheet shape is complete; there are cracks on the surface, and there is a sticking phenomenon /
  • Samples 22 to 29 are large-format ⁇ -nicotinamide mononucleotide orally disintegrating tablets containing only gelatin and aspartame. It can be seen from the test results of physical and chemical properties that the large-scale ⁇ -nicotinamide mononucleotide oral disintegrating tablets of samples 23 to 28 (weight percentage of gelatin are 2%-8.5%) are in good shape and have a short disintegration time; The sheet shape of 22 is fragile, and the sample 29 has the problems of cracks on the surface and sticking to the bottom. Compared with the samples 23 to 28, the molding effect is not good.

Abstract

A β-nicotinamide mononucleotide freeze-dried oral preparation, comprising a pharmaceutically active ingredient and a binder. The pharmaceutically active ingredient is β-nicotinamide mononucleotide or a pharmaceutically acceptable salt thereof. The binder is a gelatin. The freeze-dried oral preparation does not comprise a freeze-dried proppant. The freeze-dried oral preparation has the characteristics of good shaping, fast disintegration speed, and high drug loading capacity.

Description

一种β-烟酰胺单核苷酸冻干口服制剂A kind of β-nicotinamide mononucleotide freeze-dried oral preparation
交叉引用cross reference
本申请请求2021年2月27日提交的中国申请号202110222605.5的优先权和2021年2月27日提交的中国申请号202110222616.3的优先权，全部内容通过引用并入本文。This application claims the priority of Chinese Application No. 202110222605.5 filed on February 27, 2021 and the priority of Chinese Application No. 202110222616.3 filed on February 27, 2021, the entire contents of which are incorporated herein by reference.
技术领域technical field
本申请涉及生物医药领域中的冻干制剂领域，特别涉及一种β-烟酰胺单核苷酸冻干口服制剂。The present application relates to the field of freeze-dried preparations in the field of biomedicine, in particular to a freeze-dried oral preparation of beta-nicotinamide mononucleotide.
背景技术Background technique
β-烟酰胺单核苷酸，简称NMN，具有延缓、改善、防止衰老的作用。有研究表明，通过调节生物体内β-烟酰胺单核苷酸的水平，对心脑血管疾病、神经退行性病及老化退行性疾病等有较好的治疗和修复作用；另外，β-烟酰胺单核苷酸还可通过参与和调节机体的内分泌，起到保护和修复胰岛功能，增加胰岛素的分泌，防治糖尿病和肥胖等代谢性疾病的作用。Beta-nicotinamide mononucleotide, referred to as NMN, has the effect of delaying, improving and preventing aging. Studies have shown that by regulating the level of β-nicotinamide mononucleotide in the body, it has a good treatment and repair effect on cardiovascular and cerebrovascular diseases, neurodegenerative diseases and aging degenerative diseases; in addition, β-nicotinamide mononucleotide Nucleotides can also play a role in protecting and repairing islet function, increasing insulin secretion, and preventing and treating metabolic diseases such as diabetes and obesity by participating in and regulating the body's endocrine system.
将含β-烟酰胺单核苷酸的药物或保健品制剂制成口腔崩解片，可改善服药困难患者的用药依从性差的问题，特别是存在吐药、藏药问题的精神类疾病患者以及易拒药、呛药的儿童。与其他制备方法制得的口腔崩解片相比，冻干口腔崩解片具有崩解速度快、辅料用量少、口感好、适用于热敏性药物制备等特点。但β-烟酰胺单核苷酸冻干口腔崩解片在工艺与制备方面还存在一些问题，例如载药量较低，机械强度差等。因此，需要提供一种β-烟酰胺单核苷酸冻干口服制剂。Orally disintegrating tablets containing β-nicotinamide mononucleotide-containing medicines or health care products can improve the problem of poor medication compliance of patients with difficulty in taking medicines, especially mentally ill patients with vomiting and Tibetan medicine problems, and Children who are prone to refuse medicine and choke on medicine. Compared with the orally disintegrating tablets prepared by other preparation methods, the freeze-dried orally disintegrating tablets have the characteristics of fast disintegration speed, less amount of auxiliary materials, good taste, and are suitable for the preparation of heat-sensitive drugs. However, there are still some problems in the process and preparation of β-nicotinamide mononucleotide freeze-dried orally disintegrating tablets, such as low drug loading and poor mechanical strength. Therefore, there is a need to provide a lyophilized oral preparation of β-nicotinamide mononucleotide.
发明内容SUMMARY OF THE INVENTION
根据本说明书的一方面，提供了一种β-烟酰胺单核苷酸冻干口服制剂。 所述冻干口服制剂包括药物活性成分和粘结剂；所述药物活性成分为β-烟酰胺单核苷酸或其药学上可接受的盐，所述粘结剂为明胶，且所述冻干口服制剂不包含冻干支撑剂。According to one aspect of the present specification, there is provided a lyophilized oral preparation of β-nicotinamide mononucleotide. The freeze-dried oral preparation includes a pharmaceutical active ingredient and a binder; the pharmaceutical active ingredient is β-nicotinamide mononucleotide or a pharmaceutically acceptable salt thereof, the binder is gelatin, and the frozen The dry oral formulation does not contain a lyophilized proppant.
在一些实施例中，所述明胶选自牛皮明胶、鱼皮明胶、牛骨胶、猪骨胶、鱼骨胶中的一种或几种。In some embodiments, the gelatin is selected from one or more of cowhide gelatin, fish skin gelatin, bovine bone glue, pig bone glue, and fish bone glue.
在一些实施例中，所述冻干口服制剂还包含矫味剂。In some embodiments, the lyophilized oral formulation further comprises a flavoring agent.
在一些实施例中，所述矫味剂选自阿斯巴甜、甜蜜素、糖精钠、蔗糖素中的一种或多种。In some embodiments, the flavoring agent is selected from one or more of aspartame, sodium cyclamate, sodium saccharin, and sucralose.
在一些实施例中，所述冻干支撑剂选自糖、糖醇、氨基酸和聚维酮中一种或多种。In some embodiments, the lyophilized proppant is selected from one or more of sugars, sugar alcohols, amino acids, and povidone.
在一些实施例中，所述冻干支撑剂选自甘露醇、右旋糖酐、乳糖、海藻糖、聚维酮、山梨醇、氨基酸、普鲁兰多糖中的一种或多种。In some embodiments, the lyophilized proppant is selected from one or more of mannitol, dextran, lactose, trehalose, povidone, sorbitol, amino acid, and pullulan.
在一些实施例中，所述明胶占所述冻干口服制剂总重量的2-8.5％。In some embodiments, the gelatin comprises 2-8.5% of the total weight of the lyophilized oral formulation.
在一些实施例中，所述明胶占所述冻干口服制剂总重量的3.4-7.4％。In some embodiments, the gelatin comprises 3.4-7.4% of the total weight of the lyophilized oral formulation.
在一些实施例中，所述冻干口服制剂单位剂量内含有所述药物活性成分60-200mg。In some embodiments, the lyophilized oral formulation contains 60-200 mg of the active pharmaceutical ingredient in a unit dose.
在一些实施例中，所述冻干口服制剂为口腔崩解片。In some embodiments, the lyophilized oral formulation is an orally disintegrating tablet.
具体实施方式Detailed ways
以下是对本说明书中一些术语的定义。The following are definitions of some terms in this specification.
如本说明书中所使用的，术语“药学上可接受的盐”是指药物活性成分的形式，包括药学上可接受的有机酸和有机碱或者无机酸和无机碱的盐。As used in this specification, the term "pharmaceutically acceptable salt" refers to the form of a pharmaceutically active ingredient, including pharmaceutically acceptable salts of organic acids and bases or inorganic acids and bases.
术语“单位剂量”是指能够施用于受试者并且易于处理和包装的单一剂量。例如，单位剂量可以为单一片剂、丸剂、胶囊、锭剂、栓剂、扁囊剂、滴剂、安瓿装等。The term "unit dose" refers to a single dose which can be administered to a subject and which is easy to handle and package. For example, a unit dose can be a single tablet, pill, capsule, lozenge, suppository, cachet, drops, ampoules, and the like.
术语“规格”是指单位剂量的药物制品中药物活性成分的含量。在一些实 施例中，药物制品可以为片剂，规格可以指单片药物制品的药物活性成分的含量。例如，60mg规格片剂可为单片含60mg药物活性成分的片剂。药物活性成分的含量以药物化合物计算。若药物活性成分为该药物化合物的药学上可接受的盐，则按照该药物化合物进行折算。The term "strength" refers to the amount of active pharmaceutical ingredient in a unit dose of a pharmaceutical product. In some embodiments, the pharmaceutical product may be a tablet, and the specification may refer to the content of the pharmaceutically active ingredient in a single tablet of the pharmaceutical product. For example, a 60 mg strength tablet may be a single tablet containing 60 mg of the active pharmaceutical ingredient. The content of the active pharmaceutical ingredient is calculated as the pharmaceutical compound. If the active pharmaceutical ingredient is a pharmaceutically acceptable salt of the pharmaceutical compound, the conversion shall be carried out according to the pharmaceutical compound.
术语“大规格单位剂量”是指单位剂量的药物制品中药物活性成分的含量大于60mg。The term "large unit dose" refers to a unit dose of a pharmaceutical product containing more than 60 mg of the active pharmaceutical ingredient.
术语“水溶性药物活性成分”是指在常温或室温于水中溶解度大于1g/30mL的药物活性成分。在一些实施例中，水溶性药物活性成分包括奥司他韦、普瑞巴林、β-烟酰胺单核苷酸，及其药学上可接受的盐。The term "water-soluble pharmaceutical active ingredient" refers to a pharmaceutical active ingredient whose solubility in water is greater than 1 g/30 mL at room temperature or room temperature. In some embodiments, the water-soluble pharmaceutical active ingredient includes oseltamivir, pregabalin, beta-nicotinamide mononucleotide, and pharmaceutically acceptable salts thereof.
术语“水难溶性药物活性成分”是指在常温或室温下不溶或微溶于水的药物活性成分。在一些实施例中，水难溶性药物活性成分包括磷脂酰丝氨酸及其药学上可接受的盐。The term "poorly water-soluble pharmaceutical active ingredient" refers to a pharmaceutical active ingredient that is insoluble or slightly soluble in water at normal or room temperature. In some embodiments, the poorly water-soluble pharmaceutically active ingredients include phosphatidylserine and pharmaceutically acceptable salts thereof.
本说明书提供了一种β-烟酰胺单核苷酸冻干口服制剂，所述冻干口服制剂是大规格单位剂量的β-烟酰胺单核苷酸冻干口服制剂，且满足外观、崩解、溶出、产品稳定性等质量指标要求。本实施例的冻干口服制剂包括药物活性成分和粘结剂，药物活性成分为β-烟酰胺单核苷酸，或其药学上可接受的盐。在一些实施例中，所述冻干口服制剂包括但不限于片剂、丸剂、颗粒剂等形式的口服制剂。在一些实施例中，所述冻干口服制剂为冻干口腔崩解片。This specification provides a lyophilized oral preparation of β-nicotinamide mononucleotide, which is a large-scale unit dose lyophilized oral preparation of β-nicotinamide mononucleotide, and meets the requirements of appearance, disintegration , dissolution, product stability and other quality index requirements. The freeze-dried oral preparation of this embodiment includes a pharmaceutical active ingredient and a binder, and the pharmaceutical active ingredient is β-nicotinamide mononucleotide, or a pharmaceutically acceptable salt thereof. In some embodiments, the lyophilized oral formulation includes, but is not limited to, oral formulations in the form of tablets, pills, granules, and the like. In some embodiments, the lyophilized oral formulation is a lyophilized orally disintegrating tablet.
在一些实施例中，粘结剂可为明胶，且冻干口服制剂不包含冻干支撑剂。可用作粘结剂的明胶的非限制性实施例包括但不限于牛皮明胶、鱼皮明胶、猪皮明胶、马皮明胶、驴皮明胶、牛骨胶、鱼骨胶、猪骨胶、马骨胶、驴骨胶等。在一些实施例中，所述明胶可选自牛皮明胶、鱼皮明胶、猪皮明胶、牛骨胶、鱼骨胶、猪骨胶中的一种或多种。In some embodiments, the binder can be gelatin, and the lyophilized oral formulation does not contain a lyophilized proppant. Non-limiting examples of gelatins that can be used as binders include, but are not limited to, cowhide gelatin, fish skin gelatin, pigskin gelatin, horse skin gelatin, donkey skin gelatin, beef bone glue, fish bone glue, pig bone glue, horse bone glue, donkey bone glue Bone glue etc. In some embodiments, the gelatin may be selected from one or more of cowhide gelatin, fish skin gelatin, pigskin gelatin, bovine bone glue, fish bone glue, and pig bone glue.
在一些实施例中，明胶可占所述冻干口服制剂总重量的2-8.5％。在一些实施例中，明胶可占所述冻干口服制剂总重量的约2％、2.2％、2.4％、2.6％、2.8％、 3％、3.2％、3.4％、3.6％、3.8％、4％、4.2％、4.4％、4.6％、4.8％、5％、5.2％、5.4％、5.6％、5.8％、6％、6.2％、6.4％、6.6％、6.8％、7％、7.2％、7.4％、7.6％、7.8％、8％、8.2％、8.4％或8.5％。还包括以上述端值的组合为特征的任一范围，在此不再赘述。在一些实施例中，明胶可占所述冻干口服制剂总重量的3.4-7.4％。In some embodiments, gelatin may comprise 2-8.5% of the total weight of the lyophilized oral formulation. In some embodiments, gelatin may comprise about 2%, 2.2%, 2.4%, 2.6%, 2.8%, 3%, 3.2%, 3.4%, 3.6%, 3.8%, 4% by weight of the total lyophilized oral formulation %, 4.2%, 4.4%, 4.6%, 4.8%, 5%, 5.2%, 5.4%, 5.6%, 5.8%, 6%, 6.2%, 6.4%, 6.6%, 6.8%, 7%, 7.2%, 7.4%, 7.6%, 7.8%, 8%, 8.2%, 8.4% or 8.5%. It also includes any range characterized by a combination of the above-mentioned end values, which will not be repeated here. In some embodiments, gelatin may comprise 3.4-7.4% of the total weight of the lyophilized oral formulation.
在一些实施例中，单位剂量的所述冻干口服制剂中明胶的含量可约为2-9.25mg。在一些实施例中，单位剂量的所述冻干口服制剂中明胶的含量可约为2mg、2.5mg、3mg、3.5mg、4mg、4.5mg、5mg、5.5mg、6mg、6.5mg、7mg、7.5mg、8mg、8.5mg、9mg或9.25mg。还包括以上述端值的组合为特征的任一范围，在此不再赘述。In some embodiments, a unit dose of the lyophilized oral formulation may contain about 2-9.25 mg of gelatin. In some embodiments, the gelatin content of the lyophilized oral formulation in a unit dose may be about 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg mg, 8 mg, 8.5 mg, 9 mg or 9.25 mg. It also includes any range characterized by a combination of the above-mentioned end values, which will not be repeated here.
在一些实施例中，所述冻干口服制剂不包含选自糖、糖醇、氨基酸和聚维酮(PVP)中的一种或多种的冻干支撑剂。所排除的冻干支撑剂的非限制性实施例包括但不限于葡萄糖、蔗糖、果糖、木糖、乳糖、半乳糖、麦芽糖、异麦芽糖、甘露糖、山梨糖、海藻糖、棉子糖、普鲁兰多糖、右旋糖酐、木糖醇、山梨醇、异山梨醇、甘露醇、赤藓糖醇、麦芽糖醇、异麦芽糖醇、乳糖醇、甘氨酸、丙氨酸、缬氨酸、脯氨酸、丝氨酸、半胱氨酸、天冬酰胺、谷氨酰胺、苏氨酸、赖氨酸、精氨酸、组氨酸、PVP k30等。在一些实施例中，所排除的冻干支撑剂可选自乳糖、海藻糖、普鲁兰多糖、右旋糖酐、山梨醇、甘露醇、氨基酸、聚维酮中的一种或多种。In some embodiments, the lyophilized oral formulation does not include a lyophilized proppant selected from one or more of sugars, sugar alcohols, amino acids, and povidone (PVP). Non-limiting examples of excluded lyophilized proppants include, but are not limited to, glucose, sucrose, fructose, xylose, lactose, galactose, maltose, isomalt, mannose, sorbose, trehalose, raffinose, Lulan, dextran, xylitol, sorbitol, isosorbide, mannitol, erythritol, maltitol, isomalt, lactitol, glycine, alanine, valine, proline, serine , cysteine, asparagine, glutamine, threonine, lysine, arginine, histidine, PVP k30, etc. In some embodiments, the excluded lyophilized proppant may be selected from one or more of lactose, trehalose, pullulan, dextran, sorbitol, mannitol, amino acids, povidone.
在一些实施例中，单位剂量的所述冻干口服制剂可含有药物活性成分约60-200mg。在一些实施例中，单位剂量的所述冻干口服制剂可含有药物活性成分约60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、115mg、120mg、125mg、130mg、135mg、140mg、145mg、150mg、155mg、160mg、165mg、170mg、175mg、180mg、185mg、190mg、195mg或200mg。还包括以上述端值的组合为特征的任一范围，在此不再赘述。在一些实施例中，所述冻干口服制剂的单位剂量内可含有β-烟酰胺单核苷酸约100mg。In some embodiments, a unit dose of the lyophilized oral formulation may contain about 60-200 mg of the active pharmaceutical ingredient. In some embodiments, a unit dose of the lyophilized oral formulation may contain about 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg of the active pharmaceutical ingredient , 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg or 200mg. It also includes any range characterized by a combination of the above-mentioned end values, which will not be repeated here. In some embodiments, the lyophilized oral formulation may contain about 100 mg of beta-nicotinamide mononucleotide in a unit dose.
除上述药物活性成分和粘结剂以外，本实施例的冻干口服制剂根据需要 还包含矫味剂、香味剂、着色剂和防腐剂中的一种或多种。在一些实施例中，矫味剂包括甜味剂。本实施例包含除可作为矫味剂改善或屏蔽药物不良气味和味道也可作为冻干支撑剂的糖类、糖醇类之外的甜味剂。本实施例的矫味剂可为非糖类甜味剂，包括但不限于阿斯巴甜、甜蜜素、糖精钠、蔗糖素、天冬甜素、安赛蜜、阿力甜、纽甜、甜菊苷、奇异果素、罗汉果素、索马甜等。在一些实施例中，矫味剂选自阿斯巴甜、甜蜜素、糖精钠、蔗糖素中的一种或多种。In addition to the above-mentioned active pharmaceutical ingredients and binders, the freeze-dried oral formulation of this embodiment also contains one or more of flavoring agents, flavoring agents, coloring agents and preservatives as required. In some embodiments, flavoring agents include sweetening agents. This embodiment includes sweeteners other than sugars and sugar alcohols, which can be used as flavoring agents to improve or shield the bad smell and taste of drugs and can also be used as freeze-dried proppants. The flavoring agent of this embodiment can be a non-sugar sweetener, including but not limited to aspartame, sodium cyclamate, sodium saccharin, sucralose, aspartame, acesulfame potassium, alitame, neotame, Stevioside, thaumatin, mogrosin, thomastin, etc. In some embodiments, the flavoring agent is selected from one or more of aspartame, sodium cyclamate, sodium saccharin, and sucralose.
在一些实施例中，单位剂量的所述冻干口服制剂中矫味剂的含量可约为0.05-0.5mg。在一些实施例中，单位剂量的所述冻干口服制剂中矫味剂的含量可约为0.05mg、0.1mg、0.15mg、0.2mg、0.25mg、0.3mg、0.35mg、0.4mg、0.45mg或0.5mg。还包括以上述端值的组合为特征的任一范围，在此不再赘述。In some embodiments, the content of the flavoring agent in a unit dose of the lyophilized oral formulation may be about 0.05-0.5 mg. In some embodiments, the content of the flavoring agent in the unit dose of the lyophilized oral formulation may be about 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg or 0.5mg. It also includes any range characterized by a combination of the above-mentioned end values, which will not be repeated here.
下述实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的试验材料，如无特殊说明，均为自常规生化试剂公司购买得到的。The experimental methods in the following examples are conventional methods unless otherwise specified. The test materials used in the following examples were purchased from conventional biochemical reagent companies unless otherwise specified.
口腔崩解片外观的检测Examination of the appearance of orally disintegrating tablets
外观评价：将口腔崩解片用手指从泡罩底部用力向上取出，肉眼观察外观形貌、光滑度、是否凹陷、裂纹、粘底、萎缩等。Appearance evaluation: Take the orally disintegrating tablet upwards from the bottom of the blister with your fingers, and observe the appearance, smoothness, depression, cracks, sticking to the bottom, shrinkage, etc. with the naked eye.
崩解时间的检测Detection of disintegration time
可以使用两种方法：Two methods can be used:
1.根据USP标准，进行口腔崩解片的溶化性实验用以模拟其在口腔中的释放。将样品放入37℃的2mL水中，静止观察现象，测定完全崩解的时间。在6个独立实验中重复测定，结果用平均值给出，以秒为单位表示。1. The orally disintegrating tablet meltability test was performed to simulate its release in the oral cavity according to USP standards. Put the sample into 2 mL of water at 37°C, observe the phenomenon still, and measure the time for complete disintegration. Measurements were repeated in 6 independent experiments and results are given as mean values in seconds.
2.根据《中国药典》2015版四部通则0921崩解时限检查法中的口崩片测试法。2. According to the orally disintegrating tablet test method in the four general rules of the 2015 edition of the Chinese Pharmacopoeia 0921 Disintegration time limit inspection method.
冻干口服制剂的制备方法Preparation method of freeze-dried oral preparation
1)量取约80mL水备用，根据不同实施例的配方表，添加或不添加配方量的粘结剂。1) Measure about 80 mL of water for later use, and add or not add the binder of the formula amount according to the formula table of different embodiments.
2)根据不同实施例的配方表，称取配方量的其他组分，加入步骤1)所得混 合液中，搅拌至完全溶解；加水至100mL，搅拌均匀。2) according to the formula table of different embodiments, take by weighing other components of formula quantity, add in step 1) gained mixed solution, stir until completely dissolved; add water to 100mL, stir evenly.
3)过滤除菌后，无菌条件下将步骤2)所得混合液加入至泡罩中。3) After filtration and sterilization, the mixed solution obtained in step 2) is added to the blister under aseptic conditions.
4)冷冻干燥，制得口腔崩解片成品。上述冷冻干燥的条件显示于不同实施例的表中。4) freeze-drying to obtain the finished product of the orally disintegrating tablet. The conditions for freeze-drying described above are shown in the tables of the various examples.
实施例1.大规格β-烟酰胺单核苷酸口腔崩解片Example 1. Large-scale β-nicotinamide mononucleotide orally disintegrating tablet
用前述冻干口服制剂的制备方法制备口腔崩解片样品1至样品11，样品1至样品11的药物活性成分为β-烟酰胺单核苷酸。其中，样品1至样品3为如表1.1所示的配方1分别在表5.2所示的冻干参数1、2、3条件下制得的；样品4至样品7为如表1.1所示的配方2至配方5分别在表5.3所示的冻干参数4条件下制得的；类似的，样品8至样品11为如表1.1所示的配方2至配方5分别在表5.3所示的冻干参数5条件下制得的。共制得口腔崩解片的样品1至样品11各200片，规格为100mg/片。Orally disintegrating tablets sample 1 to sample 11 were prepared by the aforementioned preparation method of lyophilized oral preparation, and the pharmaceutical active ingredient of sample 1 to sample 11 was β-nicotinamide mononucleotide. Among them, samples 1 to 3 are prepared under the conditions of freeze-drying parameters 1, 2, and 3 as shown in Table 1.1, respectively; and samples 4 to 7 are the formulas shown in Table 1.1. 2 to formula 5 were prepared under the conditions of freeze-drying parameter 4 shown in Table 5.3; similarly, samples 8 to 11 were the freeze-dried formulas 2 to 5 shown in Table 1.1, respectively, as shown in Table 5.3 prepared under the conditions of parameter 5. A total of 200 orally disintegrating tablets from Sample 1 to Sample 11 were prepared, with a specification of 100 mg/tablet.
表1.1-配方表Table 1.1 - Recipe table
Figure PCTCN2022078131-appb-000001
Figure PCTCN2022078131-appb-000001
表1.2-冷冻干燥条件表Table 1.2 - Freeze Drying Conditions Table
Figure PCTCN2022078131-appb-000002
Figure PCTCN2022078131-appb-000002
表1.3-冷冻干燥条件表Table 1.3 - Freeze Drying Conditions Table
Figure PCTCN2022078131-appb-000003
Figure PCTCN2022078131-appb-000003
口腔崩解片样品1至样品11的理化性能检测结果见表1.4。The physical and chemical properties test results of orally disintegrating tablet samples 1 to 11 are shown in Table 1.4.
样品4、样品5、样品6和样品7为仅含矫味剂阿斯巴甜和非明胶的胶类粘结剂的大规格β-烟酰胺单核苷酸口腔崩解片。样品4至样品7底部存在不同程度的粘底现象，底部萎缩，成型效果不佳。Sample 4, Sample 5, Sample 6 and Sample 7 are large-format β-nicotinamide mononucleotide orally disintegrating tablets containing only flavoring agent aspartame and non-gelatin gum-based binder. The bottom of sample 4 to sample 7 has different degrees of sticking to the bottom, the bottom shrinks, and the molding effect is not good.
样品8、样品9、样品10和样品11为以样品4至样品7的配方为基础，经冻干参数优化后制得的大规格β-烟酰胺单核苷酸口腔崩解片。样品8至样品11仍存在不同程度的粘底以及底部萎缩等问题，优化冻干参数未明显改善样品的成型效果。Sample 8, sample 9, sample 10 and sample 11 are large-sized β-nicotinamide mononucleotide orally disintegrating tablets prepared based on the formulations of samples 4 to 7 after optimization of freeze-drying parameters. Samples 8 to 11 still have problems such as sticking to the bottom and shrinking of the bottom to different degrees, and optimizing the freeze-drying parameters did not significantly improve the molding effect of the samples.
样品1至样品3为仅含矫味剂阿斯巴甜、粘结剂明胶的大规格β-烟酰胺单核苷酸口腔崩解片。样品1至样品3均片型完整，表面光滑，无裂痕、粘底现象，成型状态较好。Samples 1 to 3 are large-scale β-nicotinamide mononucleotide orally disintegrating tablets containing only aspartame as a flavoring agent and gelatin as a binder. Samples 1 to 3 all have a complete sheet shape, a smooth surface, no cracks or sticking to the bottom, and the molding state is good.
表1.4-理化性能检测结果Table 1.4 - Physical and chemical performance test results
样品编号Sample serial number 成型外观Molded appearance
11 片型完整；表面光滑，无裂痕，无粘底现象The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom.
22 片型完整；表面光滑，无裂痕，无粘底现象The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom.
33 片型完整；表面光滑，无裂痕，无粘底现象The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom.
44 片型完整；表面出现明显裂痕，存在粘底现象，底部出现萎缩The sheet shape is complete; there are obvious cracks on the surface, there is sticking to the bottom, and the bottom is shrinking
55 片型完整；表面出现明显裂痕，存在粘底现象，底部出现萎缩The sheet shape is complete; there are obvious cracks on the surface, there is sticking to the bottom, and the bottom is shrinking
66 片型完整；表面出现明显裂痕，存在粘底现象，底部出现萎缩The sheet shape is complete; there are obvious cracks on the surface, there is sticking to the bottom, and the bottom is shrinking
77 片型完整；表面出现明显裂痕，存在粘底现象，底部出现萎缩The sheet shape is complete; there are obvious cracks on the surface, there is sticking to the bottom, and the bottom is shrinking
88 片型完整；表面出现明显裂痕，存在粘底现象，底部出现萎缩The sheet shape is complete; there are obvious cracks on the surface, there is sticking to the bottom, and the bottom is shrinking
99 片型完整；表面出现明显裂痕，存在粘底现象，底部出现萎缩The sheet shape is complete; there are obvious cracks on the surface, there is sticking to the bottom, and the bottom is shrinking
1010 片型完整；表面出现明显裂痕，存在粘底现象，底部出现萎缩The sheet shape is complete; there are obvious cracks on the surface, there is sticking to the bottom, and the bottom is shrinking
1111 片型完整；表面出现明显裂痕，存在粘底现象，底部出现萎缩The sheet shape is complete; there are obvious cracks on the surface, there is sticking to the bottom, and the bottom is shrinking
上述结果表明，含有明胶作为粘结剂的大规格β-烟酰胺单核苷酸口腔崩解片在成型效果方面优于以其他胶类作为粘结剂的大规格β-烟酰胺单核苷酸口腔崩解片。The above results show that the large-scale β-nicotinamide mononucleotide orally disintegrating tablet containing gelatin as a binder is superior to the large-scale β-nicotinamide mononucleotide with other glues as a binder in terms of molding effect. Orally disintegrating tablet.
实施例2.大规格β-烟酰胺单核苷酸口腔崩解片Example 2. Large-scale β-nicotinamide mononucleotide orally disintegrating tablet
用前述冻干口服制剂的制备方法制备口腔崩解片样品12至样品14，样品12至样品14的药物活性成分为β-烟酰胺单核苷酸。其中，样品12为如表2.1所示的配方1在对应表2.2所示的冷冻干燥条件下制得的；类似的，样品13和样品14为如表2.1所示的配方2、配方3分别在对应表2.2所示的冷冻干燥条件下制得的。共制得口腔崩解片的样品12至样品14各200片，规格为100mg/片。Orally disintegrating tablet samples 12 to 14 were prepared by the aforementioned preparation method of lyophilized oral preparation, and the active pharmaceutical ingredient of samples 12 to 14 was β-nicotinamide mononucleotide. Among them, sample 12 is prepared by formula 1 shown in Table 2.1 under the freeze-drying conditions shown in table 2.2; similarly, sample 13 and sample 14 are formula 2 and formula 3 shown in Table 2.1 respectively in Corresponding to the freeze-drying conditions shown in Table 2.2. A total of 200 orally disintegrating tablets from Sample 12 to Sample 14 were prepared, with a specification of 100 mg/tablet.
表2.1-配方表Table 2.1 - Recipe Table
Figure PCTCN2022078131-appb-000004
Figure PCTCN2022078131-appb-000004
Figure PCTCN2022078131-appb-000005
Figure PCTCN2022078131-appb-000005
注：牛骨明胶购自罗赛洛(大安)明胶有限公司；鱼皮明胶购自广州市升彤贸易有限公司；鱼骨明胶购自江西福美泰生物技术有限公司。Note: Bovine bone gelatin was purchased from Rousselot (Da'an) Gelatin Co., Ltd.; fish skin gelatin was purchased from Guangzhou Shengtong Trading Co., Ltd.; fish bone gelatin was purchased from Jiangxi Fumeitai Biotechnology Co., Ltd.
表2.2-冷冻干燥条件表Table 2.2 - Freeze Drying Conditions Table
Figure PCTCN2022078131-appb-000006
Figure PCTCN2022078131-appb-000006
表2.3-理化性能检测结果Table 2.3 - Physical and chemical performance test results
样品编号Sample serial number 成型外观Molded appearance
1212 片型完整；表面光滑，无裂痕，无粘底现象The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom.
1313 片型完整；表面光滑，无裂痕，无粘底现象The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom.
1414 片型完整；表面光滑，无裂痕，无粘底现象The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom.
口腔崩解片样品12至样品14的理化性能检测结果见表2.3。样品12至样品14为含阿斯巴甜和不同来源明胶的大规格β-烟酰胺单核苷酸口腔崩解片。上述理化性能检测结果表明，样品12至样品14均片型完整，表面光滑，无裂痕、粘底现象，成型状态较好。样品12至样品14的含有不同来源的明胶的大规格β-烟酰胺单核苷酸口腔崩解片在成型效果方面均是优异的。The test results of physical and chemical properties of orally disintegrating tablet samples 12 to 14 are shown in Table 2.3. Samples 12 to 14 are large-format β-nicotinamide mononucleotide orally disintegrating tablets containing aspartame and gelatin from different sources. The above physical and chemical properties test results show that samples 12 to 14 are all in a complete sheet shape, with smooth surfaces, no cracks and sticking to the bottom, and the molding state is good. The large-sized β-nicotinamide mononucleotide orally disintegrating tablets of samples 12 to 14 containing gelatin from different sources were all excellent in the molding effect.
实施例3.大规格β-烟酰胺单核苷酸口腔崩解片Example 3. Large-scale β-nicotinamide mononucleotide orally disintegrating tablet
用前述冻干口服制剂的制备方法制备口腔崩解片样品15至样品18，样品15至样品18的药物活性成分为β-烟酰胺单核苷酸。其中，样品15为如表3.1所示的配方1在如实施例2的表2.2所示的冷冻干燥条件下制得的；类似的，样 品16、样品17和样品18为表3.1所示的配方2、配方3、配方4分别在如实施例2的表2.2所示的冷冻干燥条件下制得的。共制得口腔崩解片的样品15至样品18各200片，规格为100mg/片。Orally disintegrating tablet samples 15 to 18 were prepared by the aforementioned preparation method of lyophilized oral preparation, and the active pharmaceutical ingredient of samples 15 to 18 was β-nicotinamide mononucleotide. Among them, sample 15 is prepared by formula 1 shown in Table 3.1 under the freeze-drying conditions shown in table 2.2 of Example 2; similarly, sample 16, sample 17 and sample 18 are the formulas shown in table 3.1 2. Formula 3 and Formula 4 were prepared under the freeze-drying conditions shown in Table 2.2 of Example 2, respectively. A total of 200 orally disintegrating tablets from Sample 15 to Sample 18 were prepared, with a specification of 100 mg/tablet.
表3.1-配方表Table 3.1 - Recipe Table
Figure PCTCN2022078131-appb-000007
Figure PCTCN2022078131-appb-000007
注：明胶150LB8和明胶180LB8购自罗赛洛(大安)明胶有限公司；胶囊用明胶购自宁夏鑫浩源生物科技股份有限公司；牛水解明胶购自上海临辰医药科技有限公司。Note: Gelatin 150LB8 and gelatin 180LB8 were purchased from Rousselot (Da'an) Gelatin Co., Ltd.; gelatin for capsules was purchased from Ningxia Xinhaoyuan Biotechnology Co., Ltd.; bovine hydrolyzed gelatin was purchased from Shanghai Linchen Pharmaceutical Technology Co., Ltd.
表3.2-理化性能检测结果Table 3.2 - Physical and chemical performance test results
样品编号Sample serial number 成型外观Molded appearance
1515 片型完整；表面光滑，无裂痕，无粘底现象The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom.
1616 片型完整；表面光滑，无裂痕，无粘底现象The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom.
1717 片型完整；表面光滑，无裂痕，无粘底现象The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom.
1818 片型完整；表面光滑，无裂痕，无粘底现象The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom.
口腔崩解片样品15至样品18的理化性能检测结果见表3.2。样品15至样品18为含阿斯巴甜和不同型号牛骨明胶的大规格β-烟酰胺单核苷酸口腔崩解片。上述理化性能检测结果表明，样品15至样品18均片型完整，表面光滑，无 裂痕、粘底现象，成型状态较好。样品15至样品18的含有不同型号牛骨明胶的大规格β-烟酰胺单核苷酸口腔崩解片，其成品成型效果好，均具有良好的理化性能，质量指标均可满足要求。The test results of the physical and chemical properties of the orally disintegrating tablet samples 15 to 18 are shown in Table 3.2. Samples 15 to 18 are large-scale β-nicotinamide mononucleotide orally disintegrating tablets containing aspartame and different types of bovine bone gelatin. The above-mentioned physical and chemical properties testing results show that the samples 15 to 18 are all sheet-shaped and complete, the surface is smooth, and there is no crack or sticking to the bottom, and the molding state is good. The large-sized β-nicotinamide mononucleotide orally disintegrating tablets of samples 15 to 18 containing different types of bovine bone gelatin have good molding effect, good physical and chemical properties, and all quality indicators can meet the requirements.
实施例4.大规格β-烟酰胺单核苷酸口腔崩解片Example 4. Large-scale β-nicotinamide mononucleotide orally disintegrating tablet
用前述冻干口服制剂的制备方法制备口腔崩解片样品19至样品21，样品19至样品21的药物活性成分为β-烟酰胺单核苷酸。其中，样品19为如表4.1所示的配方1在对应表1.2所示的冷冻干燥条件下制得的；类似的，样品20和样品21为如表4.1所示的配方2、配方3在对应表1.2所示的冷冻干燥条件下制得的。共制得口腔崩解片的样品19至样品21各200片，规格为100mg/片。Orally disintegrating tablet samples 19 to 21 were prepared by the aforementioned preparation method of lyophilized oral preparation, and the active pharmaceutical ingredient of samples 19 to 21 was β-nicotinamide mononucleotide. Among them, sample 19 is prepared by formula 1 shown in Table 4.1 under the freeze-drying conditions shown in table 1.2; similarly, sample 20 and sample 21 are formula 2 and formula 3 shown in table 4.1 in the corresponding prepared under the freeze-drying conditions shown in Table 1.2. A total of 200 orally disintegrating tablets from Sample 19 to Sample 21 were prepared, with a specification of 100 mg/tablet.
表4.1-配方表Table 4.1 - Recipe Table
Figure PCTCN2022078131-appb-000008
Figure PCTCN2022078131-appb-000008
表4.2-冷冻干燥条件表Table 4.2 - Freeze Drying Conditions Table
Figure PCTCN2022078131-appb-000009
Figure PCTCN2022078131-appb-000009
表4.3-理化性能检测结果Table 4.3 - Physical and chemical performance test results
Figure PCTCN2022078131-appb-000010
Figure PCTCN2022078131-appb-000010
Figure PCTCN2022078131-appb-000011
Figure PCTCN2022078131-appb-000011
口腔崩解片样品19至样品21的理化性能检测结果见表4.3。样品20是含明胶、冻干支撑剂甘露醇和矫味剂的β-烟酰胺单核苷酸口腔崩解片，样品21是仅含冻干支撑剂甘露醇和矫味剂的β-烟酰胺单核苷酸口腔崩解片。由理化性能检测结果可知，样品20和样品21的成型效果不佳，崩解时间相对较长，均无法达到相应的质量指标要求。样品19是仅含明胶和阿斯巴甜的β-烟酰胺单核苷酸口腔崩解片。与样品20和样品21相比，样品19的大规格β-烟酰胺单核苷酸口腔崩解片含较少的辅料且其成型效果好，崩解时间较短。The physical and chemical properties test results of orally disintegrating tablet samples 19 to 21 are shown in Table 4.3. Sample 20 is β-nicotinamide mononucleotide orally disintegrating tablet containing gelatin, lyophilized proppant mannitol and flavoring agent, and sample 21 is β-nicotinamide mononucleate containing only lyophilized proppant mannitol and flavoring agent Glycosides orally disintegrating tablets. It can be seen from the test results of physical and chemical properties that the molding effect of sample 20 and sample 21 is not good, the disintegration time is relatively long, and neither can meet the corresponding quality index requirements. Sample 19 is an orally disintegrating tablet containing only gelatin and aspartame. Compared with sample 20 and sample 21, the large-sized β-nicotinamide mononucleotide orally disintegrating tablet of sample 19 contains less excipients and has better molding effect and shorter disintegration time.
实施例5.大规格β-烟酰胺单核苷酸口腔崩解片Example 5. Large-scale β-nicotinamide mononucleotide orally disintegrating tablet
用前述冻干口服制剂的制备方法制备口腔崩解片样品22至样品29，样品22至样品29的药物活性成分为β-烟酰胺单核苷酸。其中，样品22为如表5.1所示的配方1在对应表5.2所示的冷冻干燥条件下制得的；类似的，样品23至样品29为如表5.1所示的配方2至配方8分别在对应表5.2所示的冷冻干燥条件下制得的。共制得口腔崩解片的样品22至样品29各200片，规格为100mg/片。Orally disintegrating tablet samples 22 to 29 were prepared by the aforementioned preparation method of lyophilized oral preparation, and the active pharmaceutical ingredient of samples 22 to 29 was β-nicotinamide mononucleotide. Among them, sample 22 is prepared from formula 1 shown in Table 5.1 under freeze-drying conditions corresponding to those shown in table 5.2; similarly, samples 23 to 29 are formula 2 to formula 8 shown in table 5.1 respectively in Corresponding to the freeze-drying conditions shown in Table 5.2. A total of 200 orally disintegrating tablets from Sample 22 to Sample 29 were prepared, with a specification of 100 mg/tablet.
表5.1-配方表Table 5.1 - Recipe Table
Figure PCTCN2022078131-appb-000012
Figure PCTCN2022078131-appb-000012
Figure PCTCN2022078131-appb-000013
Figure PCTCN2022078131-appb-000013
表5.2-理化性能检测结果Table 5.2 - Physical and chemical performance test results
样品编号Sample serial number 成型外观Molded appearance 崩解时间disintegration time
22twenty two 略疏松，不致密，拿取易碎裂；无裂痕，无粘底现象Slightly loose, not dense, easy to break when taken; no cracks, no sticking to the bottom //
23twenty three 片型完整；表面光滑，无裂痕，无粘底现象The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom. 6s6s
24twenty four 片型完整；表面光滑，无裂痕，无粘底现象The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom. 7s7s
2525 片型完整；表面光滑，无裂痕，无粘底现象The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom. 8s8s
2626 片型完整；表面光滑，无裂痕，无粘底现象The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom. 9s9s
2727 片型完整；表面光滑，无裂痕，无粘底现象The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom. 10s10s
2828 片型完整；表面光滑，无裂痕，无粘底现象The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom. 10s10s
2929 片型完整；表面出现裂痕，存在粘底现象The sheet shape is complete; there are cracks on the surface, and there is a sticking phenomenon //
注：“/”表示未检测崩解时间。Note: "/" indicates that the disintegration time was not detected.
口腔崩解片样品22至样品29的理化性能检测结果见表5.2。样品22至样品29为仅含明胶和阿斯巴甜的大规格β-烟酰胺单核苷酸口腔崩解片。由理化性能检测结果可知，样品23至样品28(明胶的重量百分比为2％-8.5％)的大规格β-烟酰胺单核苷酸口腔崩解片成型状态较好，崩解时间短；样品22的片型易碎，样品29存在表面具有裂痕及粘底的问题，与样品23至样品28相比，成型效果不佳。The physical and chemical properties test results of orally disintegrating tablet samples 22 to 29 are shown in Table 5.2. Samples 22 to 29 are large-format β-nicotinamide mononucleotide orally disintegrating tablets containing only gelatin and aspartame. It can be seen from the test results of physical and chemical properties that the large-scale β-nicotinamide mononucleotide oral disintegrating tablets of samples 23 to 28 (weight percentage of gelatin are 2%-8.5%) are in good shape and have a short disintegration time; The sheet shape of 22 is fragile, and the sample 29 has the problems of cracks on the surface and sticking to the bottom. Compared with the samples 23 to 28, the molding effect is not good.
上文已对基本概念做了描述，显然，对于本领域技术人员来说，上述详细披露仅仅作为示例，而并不构成对本说明书的限定。虽然此处并没有明确说明，本领域技术人员可能会对本说明书进行各种修改、改进和修正。该类修改、改进和修正在本说明书中被建议，所以该类修改、改进、修正仍属于本说明书示范实施例的精神和范围。The basic concepts have been described above. Obviously, for those skilled in the art, the above detailed disclosure is merely an example, and does not constitute a limitation of the present specification. Although not explicitly described herein, various modifications, improvements, and corrections to this specification may occur to those skilled in the art. Such modifications, improvements, and corrections are suggested in this specification, so such modifications, improvements, and corrections still belong to the spirit and scope of the exemplary embodiments of this specification.

Claims (10)

  1. 一种β-烟酰胺单核苷酸冻干口服制剂，其特征在于，所述冻干口服制剂包括药物活性成分和粘结剂；所述药物活性成分为β-烟酰胺单核苷酸或其药学上可接受的盐，所述粘结剂为明胶，且所述冻干口服制剂不包含冻干支撑剂。A β-nicotinamide mononucleotide freeze-dried oral preparation, characterized in that the freeze-dried oral preparation comprises a pharmaceutical active ingredient and a binder; the pharmaceutical active ingredient is β-nicotinamide mononucleotide or its A pharmaceutically acceptable salt, the binder is gelatin, and the lyophilized oral formulation does not contain a lyophilized proppant.
  2. 如权利要求1所述的β-烟酰胺单核苷酸冻干口服制剂，其特征在于，所述明胶选自牛皮明胶、鱼皮明胶、牛骨胶、猪骨胶、鱼骨胶中的一种或几种。The lyophilized oral preparation of β-nicotinamide mononucleotide according to claim 1, wherein the gelatin is selected from one or more of cowhide gelatin, fish skin gelatin, bovine bone glue, pig bone glue and fish bone glue kind.
  3. 如权利要求1所述的β-烟酰胺单核苷酸冻干口服制剂，其特征在于，所述冻干口服制剂还包含矫味剂。The lyophilized oral formulation of β-nicotinamide mononucleotide according to claim 1, wherein the lyophilized oral formulation further comprises a flavoring agent.
  4. 如权利要求3所述的β-烟酰胺单核苷酸冻干口服制剂，其特征在于，所述矫味剂选自阿斯巴甜、甜蜜素、糖精钠、蔗糖素中的一种或多种。The lyophilized oral preparation of β-nicotinamide mononucleotide according to claim 3, wherein the flavoring agent is selected from one or more of aspartame, sodium cyclamate, sodium saccharin, and sucralose kind.
  5. 如权利要求1所述的β-烟酰胺单核苷酸冻干口服制剂，其特征在于，所述冻干支撑剂选自糖、糖醇、氨基酸和聚维酮中一种或多种。The freeze-dried oral preparation of β-nicotinamide mononucleotide according to claim 1, wherein the freeze-dried proppant is selected from one or more of sugars, sugar alcohols, amino acids and povidone.
  6. 如权利要求5所述的β-烟酰胺单核苷酸冻干口服制剂，其特征在于，所述冻干支撑剂选自甘露醇、右旋糖酐、乳糖、海藻糖、聚维酮、山梨醇、氨基酸、普鲁兰多糖中的一种或多种。The lyophilized oral preparation of β-nicotinamide mononucleotide according to claim 5, wherein the lyophilized proppant is selected from the group consisting of mannitol, dextran, lactose, trehalose, povidone, sorbitol, amino acid , one or more of pullulan.
  7. 如权利要求1所述的β-烟酰胺单核苷酸冻干口服制剂，其特征在于，所述明胶占所述冻干口服制剂总重量的2-8.5％。The freeze-dried oral preparation of β-nicotinamide mononucleotide according to claim 1, wherein the gelatin accounts for 2-8.5% of the total weight of the freeze-dried oral preparation.
  8. 如权利要求7所述的β-烟酰胺单核苷酸冻干口服制剂，其特征在于，所述明胶占所述冻干口服制剂总重量的3.4-7.4％。The freeze-dried oral preparation of β-nicotinamide mononucleotide according to claim 7, wherein the gelatin accounts for 3.4-7.4% of the total weight of the freeze-dried oral preparation.
  9. 如权利要求1所述的β-烟酰胺单核苷酸冻干口服制剂，其特征在于，所 述冻干口服制剂单位剂量内含有所述药物活性成分60-200mg。The freeze-dried oral preparation of β-nicotinamide mononucleotide according to claim 1, wherein the unit dose of the freeze-dried oral preparation contains 60-200 mg of the active pharmaceutical ingredient.
  10. 如权利要求1-9中任一项所述的β-烟酰胺单核苷酸冻干口服制剂，其特征在于，所述冻干口服制剂为口腔崩解片。The freeze-dried oral preparation of β-nicotinamide mononucleotide according to any one of claims 1-9, wherein the freeze-dried oral preparation is an orally disintegrating tablet.
PCT/CN2022/078131 2021-02-27 2022-02-27 β-NICOTINAMIDE MONONUCLEOTIDE FREEZE-DRIED ORAL PREPARATION WO2022179635A1 (en)

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CN202110222605.5A CN114983950A (en) 2021-02-27 2021-02-27 Nicotinoyl nucleotide disintegrating tablet
CN202110222616.3 2021-02-27
CN202110222616.3A CN115054580A (en) 2021-02-27 2021-02-27 Large-scale freeze-dried orally disintegrating tablet
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