WO2022179634A1 - 一种冻干口服制剂 - Google Patents

一种冻干口服制剂 Download PDF

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Publication number
WO2022179634A1
WO2022179634A1 PCT/CN2022/078130 CN2022078130W WO2022179634A1 WO 2022179634 A1 WO2022179634 A1 WO 2022179634A1 CN 2022078130 W CN2022078130 W CN 2022078130W WO 2022179634 A1 WO2022179634 A1 WO 2022179634A1
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WIPO (PCT)
Prior art keywords
freeze
oral preparation
dried
gelatin
sample
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PCT/CN2022/078130
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English (en)
French (fr)
Inventor
张严源
吴龙昊
李鹏飞
肖立
李春娟
Original Assignee
北京兴源联合医药科技有限公司
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Priority claimed from CN202110222616.3A external-priority patent/CN115054580A/zh
Priority claimed from CN202110222605.5A external-priority patent/CN114983950A/zh
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 WO2022179634A1 publication Critical patent/WO2022179634A1/zh

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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
    • 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 application relates to the field of freeze-dried preparations in the field of biomedicine, in particular to a freeze-dried oral preparation.
  • Orally disintegrating tablet is a new type of immediate-release preparation that is convenient to take and carry. Orally disintegrating tablets can improve the problem of poor medication compliance in patients who have difficulty taking medication, especially mentally ill patients with vomiting and Vietnamese medicine problems, as well as children who are prone to refusing and choking medication. 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. At the same time, freeze-dried orally disintegrating tablets also have some problems, such as low drug loading and poor mechanical strength. Therefore, there is a need to provide a lyophilized oral formulation that overcomes the above-mentioned problems.
  • a lyophilized oral formulation includes a pharmaceutical active ingredient and a binder; the binder is gelatin, and the lyophilized 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 pharmaceutically active ingredient is water-soluble or poorly water-soluble.
  • the active pharmaceutical ingredient is oseltamivir, pregabalin, beta-nicotinamide mononucleotide, phosphatidylserine, or a pharmaceutically acceptable salt thereof.
  • 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 active pharmaceutical ingredient of the single tablet 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.
  • the lyophilized oral formulation of this embodiment includes a pharmaceutical active ingredient and a binder.
  • 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 can comprise about 2%, 2.2%, 2.4%, 2.6%, 2.8%, 3%, 3.2%, 3.4%, 3.6%, 3.8%, 4% by total weight of the 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
  • the types of active pharmaceutical ingredients in the lyophilized oral formulation include, but are not limited to, drugs, compounds, peptides, nucleotides, and the like.
  • the pharmaceutically active ingredient is water-soluble or poorly water-soluble.
  • Non-limiting examples of pharmaceutical active ingredients that can be used as the lyophilized oral formulation include, but are not limited to, analgesics, alpha blockers, anti-allergic, anti-asthmatic, anti-inflammatory, antacid, anthelmintic , antiarrhythmic drugs, antiarrhythmic drugs, antibacterial drugs, anti-anxiety drugs, anticoagulants, antidepressants, antidiabetic drugs, antidiarrheal drugs, antidiuretics, antiepileptic drugs, antifungal drugs, antigout drugs, Antihypertensive drugs, anti-incontinence drugs, anti-insomnia drugs, anti-malarial drugs, anti-migraine drugs, anti-muscarinic drugs, anti-tumor drugs, immunosup
  • the active pharmaceutical ingredient is oseltamivir or a pharmaceutically acceptable salt thereof. In some non-limiting embodiments, the active pharmaceutical ingredient is pregabalin or a pharmaceutically acceptable salt thereof. In some non-limiting embodiments, the pharmaceutical active ingredient is ⁇ -nicotinamide mononucleotide or a pharmaceutically acceptable salt thereof. In some non-limiting embodiments, the active pharmaceutical ingredient is phosphatidylserine or a pharmaceutically acceptable salt thereof.
  • 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.
  • the lyophilized oral formulation may contain about 75 mg of oseltamivir in a unit dose. In some embodiments, the lyophilized oral formulation contains about 75 mg of pregabalin in a unit dose. In some embodiments, the lyophilized oral formulation may contain about 100 mg of beta-nicotinamide mononucleotide in a unit dose. In some embodiments, the lyophilized oral formulation may contain about 100 mg of phosphatidylserine in a unit dose.
  • the freeze-dried oral preparations of this embodiment also include 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, weigh the other components of the formula, add them into the mixed solution obtained in step 1), stir until completely dissolved; add water to 100 mL, and 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 tablet samples A1 to A11 were prepared by the aforementioned preparation method of lyophilized oral preparation, and the active pharmaceutical ingredient of samples A1 to A11 was ⁇ -nicotinamide mononucleotide.
  • sample A1 to sample A3 are prepared by formula 1 shown in Table 1.1 under the conditions of freeze-drying parameters 1, 2, and 3 shown in Table 5.2;
  • sample A4 and sample A7 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 A8 to A11 were formulas 2 to 5 shown in Table 1.1, respectively, and the freeze-drying parameters shown in Table 5.3 5 conditions.
  • a total of 200 orally disintegrating tablets from sample A1 to sample A11 were prepared, with a specification of 100 mg/tablet.
  • Sample A4, sample A5, sample A6 and sample A7 are large-format ⁇ -nicotinamide mononucleotide orally disintegrating tablets containing only the flavoring agent aspartame and a non-gelatin gum-based binder.
  • the bottom of sample A4 to sample A7 has different degrees of sticking to the bottom, the bottom shrinks, and the molding effect is not good.
  • Sample A8, sample A9, sample A10 and sample A11 are large-sized ⁇ -nicotinamide mononucleotide orally disintegrating tablets prepared by optimizing the freeze-drying parameters based on the formulations of samples A4 to A7. Samples A8 to A11 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 A1 to A3 are large-scale ⁇ -nicotinamide mononucleotide orally disintegrating tablets containing only aspartame as a flavoring agent and gelatin as a binder. Samples A1 to A3 are all of complete sheet shape, smooth surface, no cracks, sticking to the bottom, and the molding state is good.
  • Sample serial number Molded appearance A1 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 A12 to A14 were prepared by the aforementioned preparation method of lyophilized oral preparation, and the active pharmaceutical ingredient of samples A12 to A14 was ⁇ -nicotinamide mononucleotide.
  • sample A12 is prepared by formula 1 shown in Table 2.1 under the freeze-drying conditions shown in table 2.2; similarly, sample A13 and sample A14 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 A12 to sample A14 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 A12 The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom. A13 The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom. A14 The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom.
  • Samples A12 to A14 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 the samples A12 to A14 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 A12 to A14 containing different sources of gelatin were all excellent in the molding effect.
  • Example 3 Large-scale ⁇ -nicotinamide mononucleotide orally disintegrating tablet
  • sample A15 to A18 were prepared by the aforementioned preparation method of lyophilized oral preparation, and the active pharmaceutical ingredient of samples A15 to A18 was ⁇ -nicotinamide mononucleotide.
  • sample A15 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 A16, sample A17 and sample A18 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 A15 to sample A18 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 A15 The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom.
  • Samples A15 to A18 are large-scale ⁇ -nicotinamide mononucleotide orally disintegrating tablets containing aspartame and different types of bovine bone gelatin.
  • the above physical and chemical properties test results show that the samples A15 to A18 are all in a complete sheet shape, with a smooth surface, no cracks and sticking to the bottom, and the molding state is good.
  • the large-scale ⁇ -nicotinamide mononucleotide orally disintegrating tablets containing different types of bovine bone gelatin from samples A15 to A18 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 A19 to A21 were prepared by the aforementioned preparation method of lyophilized oral preparation, and the active pharmaceutical ingredient of samples A19 to A21 was ⁇ -nicotinamide mononucleotide.
  • sample A19 is prepared by formula 1 shown in Table 4.1 under the freeze-drying conditions shown in table 1.2; similarly, sample A20 and sample A21 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 A19 to sample A21 were prepared, with a specification of 100 mg/tablet.
  • Sample A20 is an orally disintegrating tablet of ⁇ -nicotinamide mononucleotide containing gelatin, lyophilized proppant mannitol and flavoring agent
  • sample A21 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 A20 and sample A21 is not good, the disintegration time is relatively long, and neither can meet the corresponding quality index requirements.
  • Sample A19 is an orally disintegrating tablet containing only gelatin and aspartame. Compared with sample A20 and sample A21, the large-sized ⁇ -nicotinamide mononucleotide orally disintegrating tablet of sample A19 contains less excipients and has better molding effect and shorter disintegration time.
  • Orally disintegrating tablet samples B1 to B3 were prepared by the aforementioned preparation method of lyophilized oral preparation, and the active pharmaceutical ingredient of samples B1 to B3 was oseltamivir phosphate.
  • sample B1 is prepared by formula 1 shown in Table 5.1 under the freeze-drying conditions shown in table 5.2; similarly, sample B2 and sample B3 are formula 2 and formula 3 shown in Table 5.1 respectively in Corresponding to the freeze-drying conditions shown in Table 5.2.
  • a total of 250 orally disintegrating tablets of samples B1 to B3 were prepared, each with a specification of 75 mg/tablet (calculated as oseltamivir).
  • oseltamivir phosphate The formulation amount and unit dose of oseltamivir phosphate are calculated as oseltamivir.
  • Sample B2 is a large-strength oseltamivir phosphate orally disintegrating tablet containing gelatin, lyophilized proppant mannitol and flavoring agent
  • sample B3 is a large-strength oseltamivir phosphate containing only lyophilized proppant mannitol and flavoring agent Orally disintegrating tablet. It can be seen from the test results of physical and chemical properties that the molding effect of sample B2 and sample B3 is not good, and the disintegration time is relatively long, which cannot meet the corresponding quality index requirements.
  • Sample B1 is a large-strength orally disintegrating tablet of oseltamivir phosphate containing only gelatin and aspartame. Compared with sample B2 and sample B3, the large-sized oseltamivir phosphate orally disintegrating tablet of sample B1 contains less excipients and has better molding effect and shorter disintegration time.
  • Embodiment 6 Large-scale pregabalin orally disintegrating tablet
  • Orally disintegrating tablet sample C1 was prepared by the aforementioned preparation method of lyophilized oral preparation, and the active ingredient of sample C1 was pregabalin.
  • Sample C1 is prepared under the freeze-drying conditions corresponding to the formula shown in Table 6.1, and there are 250 orally disintegrating tablets of Sample C1, with a specification of 75 mg/tablet.
  • Sample serial number Molded appearance disintegration time C1 The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom. 8s
  • Sample C1 is a large-strength orally disintegrating tablet of pregabalin containing only gelatin and cyclamate. It can be seen from the physical and chemical properties testing that the large-sized pregabalin oral disintegrating tablet of sample C1 contains less excipients and has good molding effect and short disintegration time.
  • Example 7 Large-scale phosphatidylserine orally disintegrating tablet
  • Orally disintegrating tablet sample D1 was prepared by the aforementioned preparation method of freeze-dried oral preparation, and the active ingredient of sample D1 was phosphatidylserine. Sample D1 was prepared under the freeze-drying conditions shown in Table 7.1 with the formula shown in Table 7.2, and there were 250 orally disintegrating tablets of Sample D1, with a specification of 100 mg/tablet.
  • Sample serial number Molded appearance disintegration time D1 The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom. 10s
  • Sample D1 is a large size phosphatidylserine orally disintegrating tablet containing only gelatin. It can be seen from the test results of physical and chemical properties that the large-sized phosphatidylserine orally disintegrating tablet of sample D1 contains less excipients and has good molding effect and short disintegration time.
  • Example 8 Large-scale ⁇ -nicotinamide mononucleotide orally disintegrating tablet
  • Orally disintegrating tablets samples A22 to A29 were prepared by the preparation method of the aforementioned freeze-dried oral preparation, and the active pharmaceutical ingredients of the samples A22 to A29 were ⁇ -nicotinamide mononucleotide.
  • sample A22 is prepared from formula 1 shown in Table 8.1 under freeze-drying conditions corresponding to those shown in table 8.2; similarly, sample A23 to sample A29 are formula 2 to formula 8 shown in table 8.1 respectively in Corresponding to the freeze-drying conditions shown in Table 8.2.
  • a total of 200 orally disintegrating tablets from sample A22 to sample A29 were prepared, with a specification of 100 mg/tablet.
  • Sample serial number Molded appearance disintegration time A22 Slightly loose, not dense, easy to break when taken; no cracks, no sticking to the bottom / A23
  • the sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom.
  • 6s A24 The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom.
  • 7s A25
  • the sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom.
  • 8s A26 The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom.
  • 9s A27 The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom.
  • 10s A28 The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom. 10s
  • Samples A22 to A29 are large size ⁇ -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-sized ⁇ -nicotinamide mononucleotide oral disintegrating tablets of samples A23 to A28 (weight percentage of gelatin are 2%-8.5%) are in good shape and have a short disintegration time; The sheet shape of A22 is fragile, and the sample A29 has the problem of cracks on the surface and sticking to the bottom. Compared with the samples A23 to A28, the molding effect is not good.
  • Embodiment 9 Large-scale oseltamivir phosphate orally disintegrating tablet
  • Orally disintegrating tablet samples B4 to B8 were prepared by the aforementioned preparation method of lyophilized oral preparation, and the active pharmaceutical ingredient of samples B4 to B8 was oseltamivir phosphate.
  • sample B4 is prepared from formula 1 shown in Table 9.1 under the freeze-drying conditions shown in Table 5.2 of Example 5; similarly, samples B5 to B8 are formulas 2 to 5 shown in Table 9.1 Prepared under freeze-drying conditions as shown in Example 5, Table 5.2.
  • a total of 250 orally disintegrating tablets of samples B4 to B8 were prepared, each with a specification of 75 mg/tablet (calculated as oseltamivir).
  • oseltamivir phosphate The formulation amount and unit dose of oseltamivir phosphate are calculated as oseltamivir.
  • Sample serial number Molded appearance disintegration time B4 The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom.
  • 9s B5 The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom.
  • 9s B6 The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom.
  • 9s B7 The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom.
  • 9s B8 The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom.
  • Samples B4 to B8 are large-strength oseltamivir phosphate orally disintegrating tablets containing only gelatin and aspartame. It can be seen from the results of physical and chemical performance testing that the large-sized oseltamivir phosphate orally disintegrating tablets of sample B4 to sample B8 (weight percentage of gelatin are 2%-8.5%) are in good shape and have a short disintegration time.
  • Embodiment 10 Large-scale pregabalin orally disintegrating tablet
  • samples C2 to C6 were prepared by the aforementioned preparation method of lyophilized oral preparation, and the active pharmaceutical ingredient of samples C2 to C6 was pregabalin.
  • sample C2 is prepared from formula 1 shown in Table 10.1 under the freeze-drying conditions shown in Table 6.2 of Example 6; similarly, samples C3 to C6 are formula 2 to formula shown in Table 10.1 5 were prepared under the freeze-drying conditions shown in Table 6.2 of Example 6, respectively.
  • a total of 250 orally disintegrating tablets of samples C2 to C6 were prepared, with a specification of 75 mg/tablet.
  • Sample serial number Molded appearance disintegration time C2 The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom. 8s C3 The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom. 8s C4 The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom. 8s C5 The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom. 8s C6 The sheet shape is complete; the surface is smooth, no cracks, and no sticking to the bottom. 8s
  • Samples C2 to C6 are large-strength orally disintegrating tablets of pregabalin containing only gelatin and cyclamate. It can be seen from the test results of physical and chemical properties that the large-sized pregabalin orally disintegrating tablets of sample C2 to sample C6 (weight percentage of gelatin are 2%-8.5%) are in good shape and have a short disintegration time.

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Abstract

一种成型良好、崩解速度快、载药量高的冻干口服制剂，包括药物活性成分和粘结剂，不包含冻干支撑剂；粘结剂为明胶。

Description

一种冻干口服制剂
交叉引用
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。
技术领域
本申请涉及生物医药领域中的冻干制剂领域，特别涉及一种冻干口服制剂。
背景技术
口腔崩解片是一种服用、携带方便的新型速释制剂。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。同时，冻干口腔崩解片也存在一些问题，例如载药量较低，机械强度差等。因此，需要提供一种克服上述问题的冻干口服制剂。
发明内容
根据本说明书的一方面，提供了一种冻干口服制剂。所述冻干口服制剂包括药物活性成分和粘结剂；所述粘结剂为明胶，且所述冻干口服制剂不包含冻干支撑剂。
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。
在一些实施例中，所述冻干口服制剂还包含矫味剂。
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。
在一些实施例中，所述药物活性成分为水溶性的或水难溶性的。
在一些实施例中，所述药物活性成分为奥司他韦、普瑞巴林、β-烟酰胺单核苷酸、磷脂酰丝氨酸，或其药学上可接受的盐。
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。
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。
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％。
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％。
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。
在一些实施例中，所述冻干口服制剂为口腔崩解片。
具体实施方式
以下是对本说明书中一些术语的定义。
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。
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。
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。
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。
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。
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。
本说明书提供了一种冻干口服制剂，所述冻干口服制剂是大规格单位剂量冻干口服制剂，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。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。
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。
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％。
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。
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。
所述冻干口服制剂中的药物活性成分的类型包括但不限于药物、化合物、肽、核苷酸等。在一些实施例中，所述药物活性成分为水溶性的或水难溶性的。可作为所述冻干口服制剂的药物活性成分的非限制性实施例包括但不限于镇痛药、α阻滞剂、抗过敏药、抗哮喘药、抗炎药、抗酸药、抗蠕虫药、抗心律失常药、抗关节炎药、抗菌药、抗焦虑药、抗凝血药、抗抑郁药、抗糖尿病药、止泻药、抗利尿药、抗癫痫药、抗真菌药、抗痛风药、抗高血压药、抗失禁药、抗失眠药、抗疟药、抗偏头痛药、抗毒蕈碱药、抗肿瘤药、免疫抑制剂、抗原生动物药、抗风湿药、抗鼻炎药、抗痉挛药、抗甲状腺药、抗病毒药、抗焦虑剂、镇静药、催眠药和精神松弛剂、β-阻滞剂、抗良性过度增生药、心肌收缩药、皮质甾类、止咳药、细胞毒性剂、解充血药、利尿药、酶类、抗震颤麻痹药、组胺受体拮抗剂、绝育药、调血脂药、局麻药、神经肌肉药、硝酸盐类和抗心绞痛药、晕动病、抗痛素、抗恶心药、营养剂、阿片类止痛剂、口服疫苗、蛋白质类、肽类和重组药物等。
在一些非限制性的实施例中，所述药物活性成分为奥司他韦或其药学上可接受的盐。在一些非限制性的实施例中，所述药物活性成分为普瑞巴林或其药学上可接受的盐。在一些非限制性的实施例中，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。在一些非限制性的实施例中，所述药物活性成分为磷脂酰丝氨酸或其药学上可接受的盐。
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奥司他韦约75mg。在一些实施例中，所述冻干口服制剂的单位剂量内含有普瑞巴林约75mg。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。在一些实施例中，所述冻干口服制剂的单位剂量内可含有磷脂酰丝氨酸约100mg。
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。
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。
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。
口腔崩解片外观的检测
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。
崩解时间的检测
可以使用两种方法：
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。
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。
冻干口服制剂的制备方法
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。
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。
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。
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。
实施例1.大规格β-烟酰胺单核苷酸口腔崩解片
用前述冻干口服制剂的制备方法制备口腔崩解片样品A1至样品A11，样品A1至样品A11的药物活性成分为β-烟酰胺单核苷酸。其中，样品A1至样品A3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A4和样品A7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A8至样品A11为如表1.1所示的配方2至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A1至样品A11各200片，规格为100mg/片。
表1.1-配方表
Figure PCTCN2022078130-appb-000001
表1.2-冷冻干燥条件表
Figure PCTCN2022078130-appb-000002
表1.3-冷冻干燥条件表
Figure PCTCN2022078130-appb-000003
口腔崩解片样品A1至样品A11的理化性能检测结果见表1.4。
样品A4、样品A5、样品A6和样品A7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A4至样品A7底部存在不同程度的粘底现象，底部萎缩，成型效果不佳。
样品A8、样品A9、样品A10和样品A11为以样品A4至样品A7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A8至样品A11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。
样品A1至样品A3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A1至样品A3均片型完整，表面光滑，无裂痕、粘底现象，成型状态较好。
表1.4-理化性能检测结果
样品编号 成型外观
A1 片型完整；表面光滑，无裂痕，无粘底现象
A2 片型完整；表面光滑，无裂痕，无粘底现象
A3 片型完整；表面光滑，无裂痕，无粘底现象
A4 片型完整；表面出现明显裂痕，存在粘底现象，底部出现萎缩
A5 片型完整；表面出现明显裂痕，存在粘底现象，底部出现萎缩
A6 片型完整；表面出现明显裂痕，存在粘底现象，底部出现萎缩
A7 片型完整；表面出现明显裂痕，存在粘底现象，底部出现萎缩
样品编号 成型外观
A8 片型完整；表面出现明显裂痕，存在粘底现象，底部出现萎缩
A9 片型完整；表面出现明显裂痕，存在粘底现象，底部出现萎缩
A10 片型完整；表面出现明显裂痕，存在粘底现象，底部出现萎缩
A11 片型完整；表面出现明显裂痕，存在粘底现象，底部出现萎缩
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。
实施例2.大规格β-烟酰胺单核苷酸口腔崩解片
用前述冻干口服制剂的制备方法制备口腔崩解片样品A12至样品A14，样品A12至样品A14的药物活性成分为β-烟酰胺单核苷酸。其中，样品A12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A13和样品A14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A12至样品A14各200片，规格为100mg/片。
表2.1-配方表
Figure PCTCN2022078130-appb-000004
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。
表2.2-冷冻干燥条件表
Figure PCTCN2022078130-appb-000005
Figure PCTCN2022078130-appb-000006
表2.3-理化性能检测结果
样品编号 成型外观
A12 片型完整；表面光滑，无裂痕，无粘底现象
A13 片型完整；表面光滑，无裂痕，无粘底现象
A14 片型完整；表面光滑，无裂痕，无粘底现象
口腔崩解片样品A12至样品A14的理化性能检测结果见表2.3。样品A12至样品A14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A12至样品A14均片型完整，表面光滑，无裂痕、粘底现象，成型状态较好。样品A12至样品A14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。
实施例3.大规格β-烟酰胺单核苷酸口腔崩解片
用前述冻干口服制剂的制备方法制备口腔崩解片样品A15至样品A18，样品A15至样品A18的药物活性成分为β-烟酰胺单核苷酸。其中，样品A15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A16、样品A17和样品A18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A15至样品A18各200片，规格为100mg/片。
表3.1-配方表
Figure PCTCN2022078130-appb-000007
Figure PCTCN2022078130-appb-000008
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。
表3.2-理化性能检测结果
样品编号 成型外观
A15 片型完整；表面光滑，无裂痕，无粘底现象
A16 片型完整；表面光滑，无裂痕，无粘底现象
A17 片型完整；表面光滑，无裂痕，无粘底现象
A18 片型完整；表面光滑，无裂痕，无粘底现象
口腔崩解片样品A15至样品A18的理化性能检测结果见表3.2。样品A15至样品A18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A15至样品A18均片型完整，表面光滑，无裂痕、粘底现象，成型状态较好。样品A15至样品A18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。
实施例4.大规格β-烟酰胺单核苷酸口腔崩解片
用前述冻干口服制剂的制备方法制备口腔崩解片样品A19至样品A21，样品A19至样品A21的药物活性成分为β-烟酰胺单核苷酸。其中，样品A19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A20和样品A21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A19至样品A21各200片，规格为100mg/片。
表4.1-配方表
Figure PCTCN2022078130-appb-000009
表4.2-冷冻干燥条件表
Figure PCTCN2022078130-appb-000010
表4.3-理化性能检测结果
Figure PCTCN2022078130-appb-000011
口腔崩解片样品A19至样品A21的理化性能检测结果见表4.3。样品A20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A21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A20和样品A21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A19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A20和样品A21相比，样品A19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。
实施例5.大规格磷酸奥司他韦口腔崩解片
用前述冻干口服制剂的制备方法制备口腔崩解片样品B1至样品B3，样品B1至样品B3的药物活性成分为磷酸奥司他韦。其中，样品B1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B2和样品B3为如表5.1所示的配方2、配方3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B1至样品B3各250片，规格为75mg/片(以奥司他韦计)。
表5.1-配方表
Figure PCTCN2022078130-appb-000012
注：磷酸奥司他韦的配方量和单位剂量以奥司他韦计。
表5.2-冷冻干燥条件表
Figure PCTCN2022078130-appb-000013
表5.3-理化性能检测结果
Figure PCTCN2022078130-appb-000014
注：“/”表示未检测崩解时间。
口腔崩解片样品B1至B3的理化性能检测结果见表5.3。样品B2是含明胶、冻干支撑剂甘露醇和矫味剂的大规格磷酸奥司他韦口腔崩解片，样品B3是仅含冻干支撑剂甘露醇和矫味剂的大规格磷酸奥司他韦口腔崩解片。由理化性能检测结果可知，样品B2和样品B3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B1是仅含明胶和阿斯巴甜的大规格磷酸奥司他韦口腔崩解片。与样品B2和样品B3相比，样品B1的大规格磷酸奥司他韦口腔崩解片含较少的辅料且其成型效果好，崩解时间较短。
实施例6.大规格普瑞巴林口腔崩解片
用前述冻干口服制剂的制备方法制备口腔崩解片样品C1，样品C1的药物活性成分为普瑞巴林。样品C1为如表6.1所示的配方在对应表6.2所示的冷冻干燥条件下制得的，制得口腔崩解片的样品C1共250片，规格为75mg/片。
表6.1-配方表
Figure PCTCN2022078130-appb-000015
表6.2-冷冻干燥条件表
Figure PCTCN2022078130-appb-000016
表6.3-理化性能检测结果
样品编号 成型外观 崩解时间
C1 片型完整；表面光滑，无裂痕，无粘底现象 8s
口腔崩解片样品C1理化性能检测结果见表6.3。样品C1为仅含明胶和甜蜜素的大规格普瑞巴林口腔崩解片。由理化性能检测见过可知，样品C1的大规格普瑞巴林口腔崩解片含较少的辅料且其成型效果好，崩解时间较短。
实施例7.大规格磷脂酰丝氨酸口腔崩解片
用前述冻干口服制剂的制备方法制备口腔崩解片样品D1，样品D1的药物活性成分为磷脂酰丝氨酸。样品D1为如表7.1所示的配方在对应表7.2所示的冷冻干燥条件下制得的，制得口腔崩解片的样品D1共250片，规格为100mg/片。
表7.1-配方表
Figure PCTCN2022078130-appb-000017
表7.2-冷冻干燥条件表
Figure PCTCN2022078130-appb-000018
表7.3-理化性能检测结果
样品编号 成型外观 崩解时间
D1 片型完整；表面光滑，无裂痕，无粘底现象 10s
口腔崩解片样品D1理化性能检测结果见表7.3。样品D1为仅含明胶的大规格磷脂酰丝氨酸口腔崩解片。由理化性能检测结果可知，样品D1的大规格 磷脂酰丝氨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。
实施例8.大规格β-烟酰胺单核苷酸口腔崩解片
用前述冻干口服制剂的制备方法制备口腔崩解片样品A22至样品A29，样品A22至样品A29的药物活性成分为β-烟酰胺单核苷酸。其中，样品A22为如表8.1所示的配方1在对应表8.2所示的冷冻干燥条件下制得的；类似的，样品A23至样品A29为如表8.1所示的配方2至配方8分别在对应表8.2所示的冷冻干燥条件下制得的。共制得口腔崩解片的样品A22至样品A29各200片，规格为100mg/片。
表8.1-配方表
Figure PCTCN2022078130-appb-000019
表8.2-理化性能检测结果
样品编号 成型外观 崩解时间
A22 略疏松，不致密，拿取易碎裂；无裂痕，无粘底现象 /
A23 片型完整；表面光滑，无裂痕，无粘底现象 6s
A24 片型完整；表面光滑，无裂痕，无粘底现象 7s
A25 片型完整；表面光滑，无裂痕，无粘底现象 8s
A26 片型完整；表面光滑，无裂痕，无粘底现象 9s
A27 片型完整；表面光滑，无裂痕，无粘底现象 10s
A28 片型完整；表面光滑，无裂痕，无粘底现象 10s
样品编号 成型外观 崩解时间
A29 片型完整；表面出现裂痕，存在粘底现象 /
注：“/”表示未检测崩解时间。
口腔崩解片样品A22至样品A29的理化性能检测结果见表8.2。样品A22至样品A29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A23至样品A28(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A22的片型易碎，样品A29存在表面具有裂痕及粘底的问题，与样品A23至样品A28相比，成型效果不佳。
实施例9.大规格磷酸奥司他韦口腔崩解片
用前述冻干口服制剂的制备方法制备口腔崩解片样品B4至样品B8，样品B4至样品B8的药物活性成分为磷酸奥司他韦。其中，样品B4为如表9.1所示的配方1在如实施例5表5.2所示的冷冻干燥条件下制得的；类似的，样品B5至样品B8为如表9.1所示的配方2至5在如实施例5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B4至样品B8各250片，规格为75mg/片(以奥司他韦计)。
表9.1-配方表
Figure PCTCN2022078130-appb-000020
注：磷酸奥司他韦的配方量和单位剂量以奥司他韦计。
表9.2-理化性能检测结果
样品编号 成型外观 崩解时间
B4 片型完整；表面光滑，无裂痕，无粘底现象 9s
B5 片型完整；表面光滑，无裂痕，无粘底现象 9s
B6 片型完整；表面光滑，无裂痕，无粘底现象 9s
B7 片型完整；表面光滑，无裂痕，无粘底现象 9s
B8 片型完整；表面光滑，无裂痕，无粘底现象 9s
口腔崩解片样品B4至样品B8的理化性能检测结果见表9.2。样品B4至样品B8为仅含明胶和阿斯巴甜的大规格磷酸奥司他韦口腔崩解片。由理化性能检测结果可知，样品B4至样品B8(明胶的重量百分比为2％-8.5％)的大规格磷酸奥司他韦口腔崩解片成型状态较好，崩解时间短。
实施例10.大规格普瑞巴林口腔崩解片
用前述冻干口服制剂的制备方法制备口腔崩解片样品C2至样品C6，样品C2至样品C6的药物活性成分为普瑞巴林。其中，样品C2为如表10.1所示的配方1在如实施例6表6.2所示的冷冻干燥条件下制得的；类似的，样品C3至样品C6为如表10.1所示的配方2至配方5分别在如实施例6表6.2所示的冷冻干燥条件下制得的。共制得口腔崩解片的样品C2至样品C6各250片，规格为75mg/片。
表10.1-配方表
Figure PCTCN2022078130-appb-000021
表10.2-理化性能检测结果
样品编号 成型外观 崩解时间
C2 片型完整；表面光滑，无裂痕，无粘底现象 8s
C3 片型完整；表面光滑，无裂痕，无粘底现象 8s
C4 片型完整；表面光滑，无裂痕，无粘底现象 8s
C5 片型完整；表面光滑，无裂痕，无粘底现象 8s
C6 片型完整；表面光滑，无裂痕，无粘底现象 8s
口腔崩解片样品C2至样品C6的理化性能检测结果见表10.2。样品C2至样品C6为仅含明胶和甜蜜素的大规格普瑞巴林口腔崩解片。由理化性能检测结果可知，样品C2至样品C6(明胶的重量百分比为2％-8.5％)的大规格普瑞巴林口腔崩解片成型状态较好，崩解时间短。
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。

Claims (12)

  1. 一种冻干口服制剂，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；所述粘结剂为明胶，且所述冻干口服制剂不包含冻干支撑剂。
  2. 如权利要求1所述的冻干口服制剂，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。
  3. 如权利要求1所述的冻干口服制剂，其特征在于，所述冻干口服制剂还包含矫味剂。
  4. 如权利要求3所述的冻干口服制剂，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。
  5. 如权利要求1所述的冻干口服制剂，其特征在于，所述药物活性成分为水溶性的或水难溶性的。
  6. 如权利要求5所述的冻干口服制剂，其特征在于，所述药物活性成分为奥司他韦、普瑞巴林、β-烟酰胺单核苷酸、磷脂酰丝氨酸，或其药学上可接受的盐。
  7. 如权利要求1所述的冻干口服制剂，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。
  8. 如权利要求7所述的冻干口服制剂，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。
  9. 如权利要求1所述的冻干口服制剂，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％。
  10. 如权利要求9所述的冻干口服制剂，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％。
  11. 如权利要求1所述的冻干口服制剂，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。
  12. 如权利要求1-11中任一项所述的冻干口服制剂，其特征在于，所述冻干口服制剂为口腔崩解片。
PCT/CN2022/078130 2021-02-27 2022-02-27 一种冻干口服制剂 WO2022179634A1 (zh)

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