CN115192723A - Disintegrable solid composition and orally disintegrable solid preparation - Google Patents

Disintegrable solid composition and orally disintegrable solid preparation Download PDF

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Publication number
CN115192723A
CN115192723A CN202210346999.XA CN202210346999A CN115192723A CN 115192723 A CN115192723 A CN 115192723A CN 202210346999 A CN202210346999 A CN 202210346999A CN 115192723 A CN115192723 A CN 115192723A
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gelatin
solid composition
disintegrating
disintegrating solid
agent
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CN202210346999.XA
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Inventor
钱桦江
张茜
李雄
罗欢
蒋钰
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Suzhou Enhua Biomedical Technology Co ltd
Nhwa Pharmaceutical Corp
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Suzhou Enhua Biomedical Technology Co ltd
Nhwa Pharmaceutical Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • 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
    • A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2063—Proteins, e.g. gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2068—Compounds of unknown constitution, e.g. material from plants or animals

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
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  • Nutrition Science (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a disintegrable solid composition and an orally disintegrable solid preparation. The disintegrating solid composition comprises hydrophilic colloid with gel strength above 120 freezing force, and preferably also comprises disintegrating agent, especially L-HPC and CMC-Na or cross-linked CMC-Na as disintegrating agent. The disintegrating solid composition provided by the present invention uses gelatin having an appropriate freezing force as a freeze-dried scaffold and L-HPC and CMC-Na or cross-linked CMC-Na as a disintegrant, and due to their synergistic effects, can impart excellent tablet hardness and disintegration required for various disintegrating tablets, and can obtain excellent formability when preparing tablets.

Description

Disintegrable solid composition and orally disintegrable solid preparation
The present application claims the priority of prior applications of patent application nos. CN202110374537.4 and CN202110503420.1, which were filed in the intellectual property office of china at 2021, 04, 07 and 2021, 05, 10, respectively, and the names of the invention are "disintegrating composition and orally disintegrating solid preparation". The entire contents of said prior application are incorporated by reference into the present application.
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a disintegrating solid composition and an oral disintegrating solid preparation.
Background
Disintegrating tablets disintegrate readily in the body (e.g. in the mouth) after administration. If the orally disintegrating tablet is administered orally, it is generally desirable that the disintegration time in the oral cavity is within 1 to 30 seconds without chewing. Orally disintegrating tablets are very valuable tablets for the user, especially for persons with poor swallowing abilities, such as infants and adults, because these tablets can be taken without water.
There is a need for a formulation for such tablets that retains its shape during handling and undergoes minimal crushing and breakage. Therefore, one aspect of pharmaceutical research on tablets is the need for increased hardness. However, if only high hardness is provided, it is impossible to obtain the intended use as a pharmaceutical preparation, because this may result in degradation or denaturation of the active ingredient or change in the function of the functional particles. However, compression molding under high pressure while the hardness is sought after is generally increased, but actually there are many inconveniences in manufacturing pharmaceutical preparations due to the increase in compression molding pressure. For example, many physiologically active ingredients are known to lose activity when compression molded under high pressure.
Therefore, development of tablets is required to ensure that the hardness of the tablets themselves is sufficiently high to prevent functional changes of functional particles due to compression, and to have an appropriate oral disintegration time. In addition, with respect to orally disintegrating tablets, it is further considered whether or not there is a noticeable foreign body sensation in the oral cavity, and the like.
Disclosure of Invention
The invention aims to provide a disintegrating solid composition, in particular an orally disintegrating solid preparation, which has high hardness, low disintegration time and good clinical application prospect.
In one aspect, the present invention provides a disintegrating solid composition comprising (a) a hydrocolloid having a freezing point of 120 bloom or higher, the hydrocolloid being selected from at least one of starch, gelatin, donkey-hide gelatin, deer-horn gelatin and peach gum, and the hydrocolloid constituting 1 to 25% by weight, for example 1 to 20% by weight, preferably 2 to 15% by weight, more preferably 3 to 12% by weight, of the total weight of the solid composition.
Further preferably, the hydrophilic colloid is gelatin and/or starch; preferably the gelatine has a motility of 220 or more bloom, more preferably 220 to 250 bloom.
In a preferred embodiment, the disintegrating solid composition of the present invention further comprises a disintegrant selected from at least one of microcrystalline cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, sodium croscarmellose, and crospovidone; preferably, the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose (L-HPC), sodium carboxymethyl cellulose (CMC-Na), and croscarmellose sodium.
In a preferred embodiment of the present invention, the disintegrating solid composition comprises gelatin and a disintegrating agent, wherein the mass ratio of the gelatin to the disintegrating agent is (1-5: 1, preferably (1-2: 1; the gelatin content accounts for 3-12%, preferably 5-7% of the total mass of the solid composition;
further preferably, the disintegrant is low-substituted hydroxypropyl cellulose or a combination of (b 1) sodium carboxymethyl cellulose and/or croscarmellose sodium, and (b 2) low-substituted hydroxypropyl cellulose, and (b 1): (b2) The mass ratio of (1) to (5) is (0.6 to 1), preferably (0.7 to 3) to 1, and more preferably (1 to 3) to 1.
In a preferred embodiment of the present invention, the disintegrating solid composition comprises gelatin and a disintegrant which is croscarmellose sodium; the mass ratio of the gelatin to the disintegrant is (5-25) to 1, preferably (12-23) to 1; the gelatin content accounts for 3-12% of the total mass of the solid composition.
More preferably, when the freezing force of the gelatin is 120 bloom, the mass ratio of the gelatin to the croscarmellose sodium is (20-25): 1, preferably (23-24): 1, and the gelatin content accounts for 10-12% of the total mass of the solid composition.
More preferably, when the freezing force of the gelatin is 220 to 250 bloom, the mass ratio of the gelatin to the croscarmellose sodium is (5 to 13): 1, preferably (12 to 13): 1, and the gelatin content is 3 to 7%, preferably 5 to 7%, for example, 5.6%,5.7%,5.8%, or 5.9% of the total mass of the solid composition.
In another preferred embodiment of the present invention, the disintegrating solid composition comprises gelatin and a disintegrant. Wherein the disintegrant is a combination of (b 1) sodium carboxymethylcellulose and (b 2) low-substituted hydroxypropylcellulose, and (b 1): the mass ratio of (b 2) is (1-3) to 1; the mass ratio of the gelatin to the disintegrant is (1-2) to 1; the gelatin content accounts for 5-7% of the total mass of the solid composition.
In one embodiment of the present invention, the disintegrating solid composition further comprises at least one of a filler, a lubricant, and a protective agent.
When the disintegrating solid composition of the present invention further contains a filler, the mass of the filler is usually 70 to 98%, preferably 80 to 95%, and more preferably 80 to 90% of the total mass of the solid composition. The bulking agent contains at least one of mannitol, erythritol, xylitol, trehalose, lactose, maltose, maltitol, glucose, sucrose, fructose, and sorbitol, preferably mannitol, erythritol, xylitol, trehalose, or lactose. In the present invention, the filler is preferably mannitol and/or lactose, particularly preferably a mixture of mannitol and lactose, wherein the mannitol and lactose may be mixed in any ratio, and the mass ratio of lactose to mannitol is preferably 1 (4-10), preferably 1 (4-8), more preferably 1 (5.5-6.5).
Therefore, in a preferred embodiment of the present invention, the disintegrating solid composition further comprises mannitol and lactose, wherein the total content of mannitol and lactose accounts for 80-95% of the total mass of the solid composition, and the mass ratio of lactose to mannitol is 1 (4-8), preferably 1 (5.5-6.5).
When the disintegrating solid composition of the present invention further comprises a lubricant, the mass of the lubricant is 0.0001% to 5%, more preferably 0.1% to 5%, and particularly preferably 2% to 3% of the total mass of the solid composition. The lubricant comprises at least one of magnesium stearate, silicon dioxide, talc, polyethylene glycol (PEG), stearic acid, preferably polyethylene glycol, particularly preferably PEG1000, PEG2000, and the like.
Therefore, in a preferred embodiment of the present invention, the disintegrating solid composition further comprises PEG1000, and the content of the PEG1000 is 0.1% to 5%, preferably 2% to 3%, of the total mass of the solid composition.
When the disintegrating solid composition of the invention further comprises a protective agent, the mass of the protective agent accounts for 0.001-8% of the total mass of the solid composition, and is more preferably 0.5-8%; the protective agent comprises at least one of amino acids of glycine, alanine, valine, leucine, isoleucine, serine, threonine, aspartic acid, glutamic acid, asparagine, glutamine, lysine, arginine, cysteine, methionine, phenylalanine, histidine, tryptophan or proline, or salts thereof, preferably glycine, lysine, arginine or histidine.
Therefore, in a preferred embodiment of the present invention, the disintegrating solid composition further comprises glycine, and the content of glycine is 0.5 to 8%, preferably 2 to 6%, of the total mass of the solid composition.
In a preferred embodiment, the invention provides a disintegrating solid composition, which comprises 5-7% of gelatin, a disintegrating agent, 80-95% of a filling agent and 2-3% of a lubricating agent, wherein the mass ratio of the gelatin to the disintegrating agent is (1-2): 1; the lubricant is PEG1000, the filler is mannitol and lactose, the mass ratio of the mannitol to the lactose is 1 (5.5-6.5), the disintegrant is L-HPC, and the freezing force of the gelatin is 220-250; optionally, glycine of 5-8% is also included.
In a preferred embodiment, the invention provides a disintegrating solid composition, which comprises 5-7% of gelatin, a disintegrating agent, 80-95% of a filling agent and 2-3% of a lubricating agent, wherein the mass ratio of the gelatin to the disintegrating agent is (1-2): 1; the lubricant is PEG1000, the filler is mannitol and lactose, the mass ratio of the mannitol to the lactose is 1 (5.5-6.5), the disintegrant is L-HPC and CMC-Na, wherein the mass ratio of the CMC-Na to the L-HPC is 1-3: 1, preferably 1.2-1.5: 1, and the freezing force of the gelatin is 220-250; optionally, glycine of 5-8% is also included.
In a preferred embodiment, the invention provides a disintegrating solid composition, which comprises 10-12% of gelatin, a disintegrating agent, 80-95% of a filling agent and 2-3% of a lubricating agent, wherein the mass ratio of the gelatin to the disintegrating agent is (23-24): 1; the lubricant is PEG1000, the filler is mannitol and lactose, the mass ratio of the mannitol to the lactose is 1 (5.5-6.5), the disintegrant is CMC-Na or cross-linked CMC-Na, and the jelly strength of the gelatin is 120; optionally, glycine of 5-8% is also included.
In a preferred embodiment, the invention provides a disintegrating solid composition, which comprises 3-7% of gelatin, a disintegrating agent, 80-95% of a filling agent and 2-3% of a lubricating agent, wherein the mass ratio of the gelatin to the disintegrating agent is (12-13): 1; the lubricant is PEG1000, the filler is mannitol and lactose, the mass ratio of the mannitol to the lactose is 1 (5.5-6.5), the disintegrant is CMC-Na or cross-linked CMC-Na, and the freezing force of the gelatin is 220-250; optionally, glycine of 5-8% is also included.
In another aspect of the present invention, there is also provided an orally disintegrating solid preparation comprising a bioactive ingredient and the disintegrating solid composition of the present invention, wherein the content of the bioactive ingredient is 50% or less, preferably 20% or less, such as 2 to 20%, or 0.2 to 2.5% by weight of the solid preparation.
Preferably, the bioactive component is a drug effect component; further preferably, the bioactive ingredient is a central nervous system drug; <xnotran> , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , . </xnotran>
In a preferred embodiment of the invention, the orally disintegrating solid formulation, once placed in the oral cavity, dissolves in a period of less than 15 seconds, preferably in less than 10 seconds, or less than 5 seconds, or less than 2 seconds.
In a preferred embodiment of the present invention, the orally disintegrating solid preparation has a hardness of 3N or more, preferably 4N or more, or 7N or more, or 8N or more, and most preferably 8 to 9N.
It is particularly preferred that the orally disintegrating solid preparation dissolves in a period of less than 5 seconds once placed in the oral cavity, and that the dosage form has a hardness of 8 to 9N.
The orally disintegrating solid preparation of the present invention may be any of a sublingual tablet, a chewable tablet, a fudge, an oral patch, an oral adhesive tablet, and an oral film.
In another aspect of the invention, the preparation method of the disintegrating solid composition or the oral disintegrating solid preparation is also provided, which comprises the steps of adding the hydrophilic colloid into the solvent with the temperature of 30-60 ℃, stirring and dissolving completely, cooling to room temperature, optionally adding the disintegrating agent, the filling agent, the lubricating agent, the protective agent and the bioactive ingredient, stirring uniformly, sampling, injecting into an aluminum-plastic bubble cap, and processing by adopting a thermal processing mode or a solvent evaporation or sublimation mode.
Unless otherwise indicated, implicit from the context, or customary in the art, all parts and percentages herein are based on weight and the testing and characterization methods used are in step with the filing date of the present application. To the extent that a definition of a particular term disclosed in the prior art is inconsistent with any definition provided herein, the definition of the term provided herein controls.
The words "preferred", "preferably", "more preferred", and the like, in the present invention, refer to embodiments of the invention that may provide certain benefits, under certain circumstances. However, other embodiments may be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, nor is it intended to exclude other embodiments from the scope of the invention. The sources of the components not mentioned in the present invention are all commercially available.
Unless otherwise stated, the adjuvants mentioned in the present invention, such as fillers, disintegrants, lubricants, protectants, hydrogels, etc., are pharmaceutical adjuvants and have meanings in line with the conventional meanings in the art, such as in line with the interpretation of terms in pharmacopoeia or pharmaceutical adjuvant handbooks.
The "total mass of the solid composition" in the present invention refers to the total mass of the excipients and the bioactive ingredients in the disintegrating solid composition, i.e., the dry weight after removing the solvent (e.g., water).
After earnest research to solve the problems, the inventor discovers that when the hydrophilic colloid with certain gel strength and the optimized disintegrating agent are used in combination, and particularly when the disintegrating agent is selected from L-HPC and CMC-Na, the obtained finished product is not crushed, not cracked and has no residue under the synergistic action of the L-HPC and the CMC-Na, the hardness of 8-9N and the disintegration time of about 2s can be achieved, and meanwhile, the inventor has better mouthfeel and avoids the inactivation of active ingredients.
The inventor has made intensive studies, and has considered that the feeling of grittiness in the mouth caused by the insolubility of microcrystalline cellulose and the influence of the physical properties of the effective components on the itself, which greatly affects the disintegrability of the drug; the inventors then tried to substitute starch in a solution without microcrystalline cellulose, but it is known that too high a starch content results in a tablet with poor compression formability. In the subsequent studies, the inventors have unexpectedly found that a desired disintegration property can be obtained by using a specific gelatin even without containing starch, but the hardness of a solid preparation is difficult to balance, but when the inventors used it together with a disintegrant having a certain composition after further studies, a disintegrating composition having a high hardness and an excellent disintegration time and an excellent appearance quality is unexpectedly obtained, and the composition can be used as a formulation platform for compatibility with various types of pharmaceutically active ingredients.
In a first aspect, the present invention provides a disintegrating solid composition comprising (a) a hydrocolloid having a freezing force of 120 bloom or more, (b) a disintegrant, and (c) a filler; wherein the hydrophilic colloid is selected from at least one of starch, gelatin, donkey-hide gelatin, deer-horn gelatin and peach gum, and accounts for 1-20% of the total mass of the composition.
Hydrophilic colloid with freezing force above 120 bloom >
Hydrocolloids are a class of colloids with a strong affinity for water, which include, for example, animal gums, starches, gums and proteins. Among them, examples of the animal gum include gelatin, donkey-hide gelatin, and antler gum, and examples of the gum include peach gum, konjac gum, and carrageenan.
The hydrophilic colloid suitable for the present invention is preferably at least one of starch, gelatin, donkey-hide gelatin, deer-horn gelatin, peach gum. The amount of the hydrophilic colloid is preferably 1 to 20% by weight, more preferably 2 to 10%, further preferably 2 to 8%, further preferably 5 to 8% of the total mass of the composition. When a plurality of the above-described preferred hydrocolloids are used in admixture, the total amount of the admixture generally remains the same as when used alone, and the respective mixing ratio may be any ratio. Gelatin and/or starch are the most suitable hydrocolloids for the present invention by investigation, wherein the gelatin used is an ampholyte which acts as a freeze-dried scaffold to coagulate charged microparticles into clumps.
In further studies on gelatin, the inventors have surprisingly found that by selecting gelatin of different freezing forces, tablets with appropriate disintegration times and different hardness can be obtained. Preferably, the gelatine has a freezing point of between 100 and 250 bloom, more preferably between 120 and 225 bloom, including, for example, 150 bloom, 160 bloom, 180 bloom, 200 bloom, 220 bloom, 250 bloom; among them, gelatin having a freezing force of 220 bloom is more preferable.
The term "freezing force" as used herein means a force in terms of bloomag (blumm) applied when a freezing surface containing 6.67% or 12.5% of gelatin is pressed into a cylindrical shape having a diameter of 12.7mm formed by dissolving and condensing a solution in a special freezing force test flask under a predetermined test environment for a certain period of time, and the freezing surface contains 4mm of gelatin. In one embodiment, a mixture of gelatin and starch is used as a hydrocolloid, and it is found that it is difficult to obtain a tablet with high hardness by compounding gelatin with starch with different freezing forces, because in the experiment, considering the water insolubility of starch, the taste is considered, and simultaneously the quality of starch cannot be improved to obtain better synergy with gelatin, which is a common problem in oral tablets containing starch; in addition, since the starch has poor formability due to the preparation process using lyophilization, the increased content may cause the tablet to be cracked or broken.
Further studies have found that in embodiments not comprising starch as the hydrocolloid, different adjustments to the disintegrant have an effect not only on the disintegration time but also on the hardness and the degree of residue.
< b) disintegrating agent >
The disintegrant is a substance which can cause the tablet to rapidly break into fine particles in contact with a liquid, and most of the substances have good water absorption and expansibility, thereby realizing the disintegration of the tablet.
As for the disintegrant in the present invention, it is preferable by study that the disintegrant includes at least one selected from the group consisting of microcrystalline cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, sodium croscarmellose, and crospovidone. More preferred disintegrants include low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium, and crospovidone, and these preferred disintegrants may be used alone or in combination of two or more; when used alone, the amount is 0.5-15%, such as 3-12%, 1-10%, preferably 3-6% or 5-7% of the total weight of the composition, and excessive amounts of these disintegrants can cause the tablet to swell to form a water-resistant layer, which affects disintegration; when a plurality of disintegrants which are preferred as described above are used in combination, the total amount of the mixture thereof is generally kept to be the same as that when used alone, and the respective mixing ratio may be any ratio.
In a preferred embodiment, the disintegrant comprises (b 1) sodium carboxymethylcellulose and/or croscarmellose sodium; and (b 2) low-substituted hydroxypropylcellulose. It is further preferable that when the disintegrant is (b 1) sodium carboxymethylcellulose and (b 2) low-substituted hydroxypropylcellulose, in particular, (b 1): (b2) When the mass ratio of (2) to (3) is (0.6 to 5): 1, the overall performance is the best, and (0.7 to 3): 1 is more preferable, 1 to 3): 1 is further preferable, and (1 to 2): 1 is further preferable.
More preferably, the disintegrant used is (b 1) sodium carboxymethyl cellulose and (b 2) low-substituted hydroxypropyl cellulose, as compared to microcrystalline cellulose or sodium carboxymethyl cellulose alone as the disintegrant.
Among them, sodium carboxymethylcellulose is generally classified into four types, i.e., an extra-high viscosity, a medium viscosity, and a low viscosity, according to the viscosity thereof, and generally, the lower the viscosity thereof, the smaller the molecular weight thereof, and the lower the substitution degree thereof.
It has been unexpectedly found that the use of different degrees of substitution of sodium carboxymethylcellulose and gelatin in the present system has different properties, such as impact on mouthfeel and residual levels; the sodium carboxymethylcellulose with the proper substitution degree is presumed to enable the distribution of water in the network structure of the gelatin and the filler to be more uniform, the volume of ice crystals formed in the freeze-drying condensation process is smaller, and the damage influence on the microstructure of the tablet is smaller; conversely, if the degree of substitution is too low, poor water solubility will result in poor taste of the tablet.
The degree of substitution of the sodium carboxymethylcellulose of the present invention is between 0.5 and 2.5, preferably between 0.6 and 1.2, more preferably between 0.65 and 0.85, most preferably 0.7, in view of the final combination of properties of the tablet. The viscosity is 25 to 1500mpa.s, more preferably 25 to 1000mpa.s, still more preferably 25 to 800mpa.s, and for example, the viscosity is preferably any value selected from 25, 50, 100, 200, 300, 400, 500, 600, 700, and 800, or any value included in a range having any two of these values as a starting point and an ending point.
Sodium carboxymethylcellulose having the above-mentioned preferred degree of substitution of 0.6 to 0.9 is commercially available, and examples thereof include, but are not limited to, 7HF4XF PH, 7HF PH, 7H3SF PH, 7HOF PH, 7M31F PH, 7MF PH, 7M8SF PH, 7M1F PH, 7LF PH, 7L2P, and the like.
The substitution degree of the sodium carboxymethyl cellulose refers to the number of hydroxyl groups on each glucose unit which are substituted by ether groups on average, and the theoretical maximum substitution degree is 3; the viscosity of sodium carboxymethylcellulose is short for dynamic viscosity, and the unit is pascal second (Pas) or millipascal second (mpa.s), and is a sodium carboxymethylcellulose aqueous solution with the mass fraction of 2%, and is measured at 25 ℃ +/-0.2 ℃.
In the research, as the sodium carboxymethyl cellulose partially neutralizes 220 frozen gelatin molecules, intermolecular repulsion is reduced, molecular chains are not completely unfolded, and the low-substituted hydroxypropyl cellulose competes for cross-links among the gelatin molecules through the cross-links, so that the disintegration can be synergistically promoted and certain hardness is improved together with specific gelatin, and the result shows that the hardness, the disintegration time, the mouthfeel and the like are good when the mass ratio of (b 1) the sodium carboxymethyl cellulose with proper substitution degree and viscosity to (b 2) the low-substituted hydroxypropyl cellulose is (0.7-3): 1; the inventor has the surprise that the composition obtained by the disintegrant with the proportion has almost no residue on a packing material such as an aluminum-plastic blister after being peeled off, and is very suitable for preparing disintegrating tablets by a freeze-drying process.
< Filler >
Fillers are generally used to facilitate tablet formation as a material to fill the weight or volume of the tablet, and include, for example, sugars or sugar alcohols such as lactose, sucrose, fructose, dextrose, mannitol, xylitol, erythritol, sorbitol, maltitol; cellulose derivatives such as microcrystalline cellulose and lignocellulose; starches such as starch, pregelatinized starch, corn starch, and modified corn starch.
The filler suitable for the present invention is preferably a sugar or sugar alcohol compound, and examples thereof include mannitol, erythritol, xylitol, trehalose, lactose, maltose, maltitol, glucose, sucrose, fructose, mannose, and sorbitol, and preferably mannitol, erythritol, xylitol, trehalose, and lactose; these fillers may be used alone or in combination of 2 or more, and the filler is preferably 70 to 98%, more preferably 80 to 95%, and still more preferably 80 to 90% of the total mass of the composition. When a plurality of fillers which are the above-mentioned preferred fillers are used in combination, the total amount of the mixture is generally kept to be the same as that when used alone, and the respective mixing ratio may be any ratio. In one embodiment, the filler is lactose and mannitol, wherein the mass ratio of lactose to mannitol is 1 (4-10), preferably 1 (4-8), more preferably 1 (5.5-6.5).
In the system, gelatin with proper freezing force and disintegrant act to form a composite system, and the filler is wrapped in the composite system to play a role in supporting a network structure.
The amount of each component used in the disintegrating solid composition of the present invention is appropriately determined depending on the type of each component, the type of the object to be used, and the use. Preferably, the disintegrating solid composition comprises 1 to 20 percent of (a) hydrophilic colloid with the freezing force of more than 120 Brumk, (b) disintegrating agent 0.5 to 15 percent and (c) filling agent 70 to 98 percent by weight; more preferably, the composition comprises 2 to 10% of (a) a hydrophilic colloid having a freezing point of 120 bloom or higher, (b) 1 to 10% of a disintegrant, and 80 to 95% of (c) a filler.
The disintegrating solid composition of the present invention may further contain at least one additive selected from lubricants and protective agents known to those skilled in the art, in addition to the above-mentioned (a) hydrophilic colloid having a freezing point of 120 bloom or higher, (b) disintegrating agent, and (c) filler.
As the lubricant, the present invention is not particularly limited thereto, and may be any one conventionally used in the art, preferably magnesium stearate, silicon dioxide, talc, polyethylene glycol, stearic acid, and these preferred lubricants can significantly increase the fluidity between particles of the composition and improve the state of the filler, more preferably polyethylene glycol, including but not limited to PEG100, PEG200, PEG400, PEG800, PEG1000, PEG1500, PEG2000, PEG4000, and most preferably PEG1000. In the composition of the present invention, these lubricants may be used alone or in combination of a plurality of the above; the content of the lubricant in the composition is not limited, and may be 0 to 5% (w/w), preferably 0.1 to 5% (w/w), more preferably 1 to 5% (w/w), based on the total mass of the composition.
The protective agent of the present invention is not particularly limited thereto, and any protective agent conventionally used in the art may be used, and amino acids or salts thereof of glycine, alanine, valine, leucine, isoleucine, serine, threonine, aspartic acid, glutamic acid, asparagine, glutamine, lysine, arginine, cysteine, methionine, phenylalanine, histidine, tryptophan, and proline, or amino acids and derivatives thereof such as peptides, proteins containing these amino acids as constituent amino acids are preferable, and glycine, lysine, arginine, or histidine are more preferable. In the composition of the present invention, these protective agents may be used alone or in combination of plural kinds thereof, preferably glycine; the content of the protective agent in the composition is not limited, and may be 0 to 8% (w/w), preferably 0.5 to 8% (w/w), more preferably 2 to 8% (w/w), based on the total mass of the composition.
When the disintegrating solid composition of the present invention contains at least one additive selected from a lubricant and a protective agent in addition to the above-mentioned (a) hydrophilic colloid having a freezing point of 120 bloom or higher, (b) disintegrating agent, and (c) filler, it is preferable that the disintegrating solid composition contains 1 to 20% of the (a) hydrophilic colloid having a freezing point of 120 bloom or higher, (b) disintegrating agent in an amount of 0.5 to 15%, 70 to 98% of the (c) filler, 0 to 5% of the lubricant, and 0 to 8% of the protective agent, in terms of the total weight of the disintegrating solid composition.
More preferably, the composition comprises 1 to 20% of (a) a hydrophilic colloid having a freezing force of 120 bloom or more, (b) 0.5 to 15% of a disintegrating agent, (c) 80 to 95% of a filler, (c) 0.1 to 5% of a lubricant, and (c) 0.5 to 8% of a protective agent.
More preferably, the composition comprises 2 to 10% of (a) a hydrophilic colloid having a freezing force of 120 bloom or more, (b) a disintegrating agent, 80 to 95% of (c) a filler, 0.1 to 5% of a lubricant, and 0.5 to 8% of a protective agent.
More preferably, the composition comprises 2 to 8% of (a) a hydrophilic colloid having a freezing force of 120 bloom or more, (b) 3 to 6% of a disintegrating agent, (c) 80 to 90% of a filler, (c) 0.1 to 5% of a lubricant, and (c) 0.5 to 8% of a protective agent.
More preferably, the composition comprises 2 to 8% of (a) a hydrophilic colloid having a freezing force of 120 bloom or more, (b) 3 to 6% of a disintegrating agent, (c) 80 to 90% of a filler, (c) 1 to 5% of a lubricant, and (c) 2 to 8% of a protective agent.
For the disintegrating solid composition of the present invention, the hardness is preferably more than 4N, more preferably more than 7N, further preferably more than 8N; and has a disintegration time in water of 1 to 15 seconds, more preferably 1 to 10 seconds, further preferably 1 to 5 seconds.
In the disintegrating solid composition of the present invention, any other additives known to those skilled in the art other than the above-mentioned components may be added and mixed as appropriate within a range not impairing the effects of the present invention obtained from the above-mentioned components, for example, for the purpose of improving the binding power and the characteristics of tablets to be taken. Examples of such additives include, but are not limited to, disintegrants, excipients, glidants, sweeteners, flavors, fragrances, colorants, and the like.
In a second aspect, the present invention provides the use of the disintegrating solid composition described above in compounding with a pharmaceutically effective ingredient in a stable and effective amount to form a pharmaceutical formulation.
The above-mentioned disintegrating solid composition of the present invention can be prepared very simply by methods well known in the art and conventional equipment. For example, the components can simply be physically combined by dissolving, mixing, blending, stirring or shaking until a homogeneous mixture is obtained. Then, the active ingredients are blended with each other during the processing. The pharmaceutical preparation comprising the disintegrating solid composition and the pharmaceutically active ingredient of the present invention can be obtained by physically blending the disintegrating solid composition and the pharmaceutically active ingredient in any conventional manner until the pharmaceutically active ingredient and the disintegrating solid composition are dispersed throughout the preparation. In a typical commercial implementation, this can be accomplished by freeze-dried mixing. Preferably, the pharmaceutically active ingredient may be added separately to the disintegrating solid composition in a premixed form or may be added separately to each of the dispersed components of the disintegrating solid composition.
In a third aspect, the present invention provides an orally disintegrating solid preparation comprising a biologically active ingredient (preferably a pharmaceutically active ingredient) and the disintegrating solid composition described above. The pharmaceutically active ingredient is preferably added to the disintegrable solid composition in an amount of 50w/w% or less of the preparation, more preferably 20w/w% or less of the preparation, and even more preferably 2 to 20w/w% of the preparation.
The disintegrating solid composition of the present invention may contain a bioactive ingredient (preferably, a pharmaceutically active ingredient) generally used in the art, as long as the desired effect of the present invention is not impaired. The bioactive ingredient (preferably, a pharmaceutically active ingredient) is not limited in any way, and may be any one of those effective in the field of therapeutics or prophylactics. These bioactive ingredients (preferably, pharmaceutically active ingredients) may be contained in the composition of the present invention or may be added to the formulation separately from the composition of the present invention.
The biologically active ingredient includes active compounds and compounds for veterinary and human use, including, for example but not limited to, pharmaceutical active ingredients (pharmaceutically active compounds), nutraceuticals, cosmeceuticals, cosmetics, natural products, vitamins, foods, nutraceuticals, biologicals, amino acids, proteins, nucleotides, and nucleic acids, and in preferred embodiments is suitable for oral administration.
Examples of such pharmaceutically effective ingredients include: hypnotic sedatives, sleep inducers, anxiolytics, antiepileptics, antidepressants, antiparkinson agents, psychoneurotics, central nervous system remedies, local anesthetics, skeletal muscle relaxants, autonomic nerve remedies, antipyretic, analgesic, anti-inflammatory agents, antispasmodics, antihalation agents, cardiotonics, antiarrhythmics, diuretics, hypotensive agents, vasoconstrictors, vasodilators, circulatory organ remedies, hyperlipemia remedies, respiratory promoters, antitussives, expectorants, antitussive, expectorants, bronchodilators, antidiarrheal agents, intestinal tract remedies, peptic ulcer remedies, stomach and digestive agents, antacids, purgatives, choleretic agents, digestive organ remedies, adrenal hormones, urinary organ remedies, vitamins, hemostatic agents, liver disease remedies, gout remedies, diabetes remedies, antihistamines, antibiotics, antibacterial agents, anti-malignant tumor agents, chemotherapeutics, cold syndromes, tonic health-care agents, osteoporosis remedies, etc., for example, indomethacin, diclofenac sodium, codeine, ibuprofen, phenylbutazone, oxyphenbutazone, pyripyrim (mepirizol), aspirin, ethenzamide, acetaminophen (paracetamol), aminopyrine, phenacetin, scopolamine butylbromide, morphine, etodoline, indomethacin, fenoprofen calcium, naproxen, celecoxib, valdecoxib, tramadol and the like antiinflammatory, antipyretic, antispasmodic or analgesic agents, etodolac and the like antirheumatic, isoniazid, ethambutol hydrochloride and the like antitubercular agents, isosorbide dinitrate, nitroglycerin, nifedipine, barnidipine hydrochloride, nicardipine hydrochloride, dipyridamole, amrinone, indolol hydrochloride, hydralazine hydrochloride, methyldopa, furosemide, drugs for circulatory organs such as spironolactone, guanethidine nitrate, reserpine, sulfamolol hydrochloride, lisinopril, metoprolol, pilocarpine hydrochloride, paroxetine and the like, anticonvulsants such as chlorpromazine hydrochloride, amitriptyline hydrochloride, nemorubide, haloperidol, moperone hydrochloride, perphenazine, diazepam, lorazepam, chlordiazepoxide, alprazolam, methylphenidate, milnacipran, risperidone, sodium valproate and the like, emetics such as metoclopramide, ramosetron hydrochloride, granisetron hydrochloride, ondansetron hydrochloride, azasetron hydrochloride and the like, antihistamines such as chlorphenamine maleate, diphenhydramine hydrochloride and the like, thiamine nitrate, vitamin E acetate, cyprosulfamine, pyridoxal phosphate, cobamamide, ascorbic acid, nicotinic acid, vitamins such as nicotinamide and the like, allopurinol, drugs for gout such as colchicine, proparasulindac, levosulindac and the like, hypnotic sedatives such as amobarbital, bromoisoflurane, midazolam, chloral hydrate and dexmedetomidine, anti-malignant tumors such as fluorouracil, carmofur, doxorubicin hydrochloride, cyclophosphamide and thiotepa, anti-allergic drugs such as pseudoephedrine and terfenadine, decongestants such as phenylpropanolamine and ephedrine, diabetes drugs such as acehexol, insulin, tolbutamide, desmopressin and glipizide, diuretics such as hydrochlorothiazide, poishiazide and triamterene, bronchodilators such as aminophylline, formoterol fumarate and theophylline, antitussives such as codeine phosphate, narcotine, dimesnane phosphate and dextromethorphan, antiarrhythmics such as quinidine nitrate, digitoxin, propafenone hydrochloride and procainamide, surface anesthetics such as ethyl aminobenzoate, lidocaine and cinchocaine hydrochloride, surface anesthetics such as phenytoin, phenytoin, antiepileptics such as ethosuximide and prometrone, synthetic adrenocorticosteroids such as hydrocortisone, prednisolone, triamcinolone and betamethasone, digestive system drugs such as famotidine, ranitidine hydrochloride, cimetidine, sucralfate, sulpiride, teprenone, praenotol, 5-aminosalicylate, sulfasalazine, omeprazole, lansoprazole, and the like, central nervous system drugs such as indolozin, idebenone hydrochloride, tiapride hydrochloride, dimeperazone hydrochloride, calcium homopantothenate and the like, antihyperlipidemic therapeutic agents such as pravastatin sodium, simvastatin, lovastatin, fluvastatin, atorvastatin and the like, antibiotics such as phthalazinone hydrochloride, cefotetan, josamycin hydrochloride and the like, BPH therapeutic agents such as loxacin hydrochloride, doxazosin mesylate, terazosin hydrochloride and the like, pranlukast, zafirlukast, salbutamol, ambroxol, budesonide, levosalbutamol, antiasthmin and the like, anti-sodium I derivatives such as bebestatin, anti-circulating therapeutic agents such as beraprost, various skin ulcer, anti-ulcer therapeutic agents, and the combination therapeutic agents for hypertension, and the like. The drug may be any of free form or pharmaceutically acceptable salts.
Among the above-mentioned pharmaceutically effective ingredients, particularly, central nervous system drugs are preferred as the pharmaceutically effective ingredients in the present invention, and examples of such pharmaceutically effective ingredients include the antidepressants citalopram, escitalopram oxalate, fluoxetine, fluvoxamine, paroxetine, sertraline; venlafaxine and duloxetine; peganum harmala, isoproterenol, isocarboxamides, nicotinamide, eugonin, phenelzine, selegiline, toloxatone, tranylcypromine, bromofamine, moclobemide; amitriptyline, amoxapine, bupiritigene, clomipramine, desipramine, dibenzepin, dothiepin, doxepin, imipramine, enalapril, lofelamine, melitriptyline, nortriptyline, olpimox, protiline, trametamine; maprotiline, mianserin, nefazodone, trazodone, pharmaceutically acceptable salts, isomers, and combinations thereof; the mood stabilizer is lithium carbonate, lithium orotate, lithium salt, valproic acid, divalproex sodium, valproate sodium, lamotrigine, carbamazepine, gabapentin, oxcarbazepine, topiramate, dexmedetomidine, pharmaceutically acceptable salts, isomers, and combinations thereof; the herbal antidepressant drug san john's wort; a slip; echinacea purpurea; sawing palm; holy basil; valerian root; silybum marianum; siberian ginseng; korean ginseng; withania somnifera root; nettle; ginkgo biloba; centella asiatica; ginkgo/centella asiatica; astragalus root; gold seal grass; radix Angelicae sinensis; ginseng; st.John's wort; echinacea purpurea; bilberry, green tea; hawthorn fruit; ginger, ginkgo, turmeric; olibanum; black cohosh; a cat's claw; catnip; chamomile; dandelion; holy berry; black elderberry; (ii) feverfew; garlic; horse chestnut; licorice extract; red clover flower and rhodiola rosea leaf; coleus forskohlii; passion flower; herba Euphrasiae Regelii; yohimbine; a blueberry plant; black pepper plants; centella asiatica; astragalus root; valerian poppy root and grape seed; verbena; root of Echinacea purpurea; comfrey, tranquilizers and combinations thereof; the antipsychotic agent haloperidol, chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thiopyridazine, trifluoropiperazine, metamethylpyrazine, promazine, trifluoropropylamine, levopromazine, promethazine, chlorpromazine, thiothixene, betachlorothiaton, clozapine, olanzapine, risperidone, buspirone, quetiapine, amisulpride, paliperidone, dopamine, bifeprunox (bifeprunox), norclozapine (norclozapine), aripiprazole, tetrabenazine, cannabidiol, haloperidol, loxapine, mesoridazine, molindone, pimozide, prochlorperazine, thioridazine, thiothixene, trifluoperazine, quetiapine and ziprasidone, pharmaceutically acceptable salts, isomers and combinations thereof.
The above-mentioned pharmaceutically active ingredients may be used alone or in combination of two or more. The amount of the pharmaceutically active ingredient to be used is not particularly limited as long as it is generally therapeutically effective, but is preferably 50w/w% or less, more preferably 20w/w% or less, further preferably 2 to 20w/w% or 0.2 to 2.5% based on the weight of the tablet.
The particle size of the above-mentioned pharmaceutically active ingredient is not particularly limited as long as it is not rough in the oral cavity. For example, the average particle size is preferably from 0.1 to 350. Mu.m, more preferably from 5 to 250. Mu.m, most preferably from 50 to 250. Mu.m. When the particle size is less than 0.1. Mu.m, it is difficult to exert the drug effect at a precise position, and when the particle size is more than 350. Mu.m, the feeling of discomfort in the oral cavity is increased.
Since the orally disintegrating solid preparation described above contains the disintegrating particle composition of the present invention, it has excellent properties such as hardness, disintegratability, and moldability. That is, as shown in the examples of the present specification, for example, the hardness of the orally disintegrating solid preparation is more than 4N, more preferably more than 7N, and still more preferably more than 8N; and has a disintegration time in water of 1 to 15 seconds, more preferably 1 to 10 seconds, further preferably 1 to 5 seconds.
The shape of the orally disintegrating solid preparation is not particularly limited in the present invention, and may be a tablet of any shape. More specifically, the orally disintegrating solid preparation of the present invention may be an oral tablet, a effervescent tablet, a dispensing tablet, a chewable tablet, a fudge, an buccal or sublingual tablet, a buccal patch, a buccal adhesive tablet or a buccal film. The intended effect is more suitable for any one of sublingual tablets, chewable tablets, fudgers, buccal patches, buccal adhesive tablets and buccal films.
The orally disintegrating solid preparation may further contain any other ingredient known to those skilled in the art in order to adjust various characteristics such as disintegrating ability, binding power, and feeling of taking of the tablet, within a range not impairing the intended effect of the present invention. Examples of such ingredients include glidants, inorganic excipients, sweeteners, flavors, coloring agents, and the like.
The fourth aspect of the present invention provides the above method for producing an orally disintegrating solid preparation, which may be any one of a sublingual tablet, a chewable tablet, a fudge, an oral patch, an oral adhesive tablet and an oral film, comprising the steps of: adding the hydrophilic colloid into a solvent with the temperature of 30-60 ℃, stirring and dissolving completely, cooling to room temperature, adding the disintegrating agent, the filling agent and the active ingredients, stirring uniformly, sampling, injecting into an aluminum-plastic bubble cap, and processing by adopting a thermal processing or solvent evaporation or sublimation mode to obtain the hydrophilic colloid.
In order to obtain the finished tablets with the same specification, the solvent is generally removed from the mixed material by taking a sample with the same volume under the same conditions and adopting a thermal processing or solvent evaporation mode. In order to further improve the pharmaceutical activity and to be more suitable for the pharmaceutical ingredient which forms a poorly water-soluble dihydrate in a solvent such as water, the solvent is preferably removed by lyophilization, and the solvent may be water, ethanol, propylene glycol, tert-butanol, or the like. The amount of the solvent is usually such that the total mass of the composition in the solvent is maintained at 10 to 40% by mass. In addition, when the pharmaceutically active ingredient is relatively stable, tableting may also be performed according to compression molding methods known in the art, including, but not limited to, direct tableting, indirect tableting, and the like.
Has the advantages that: the disintegrating solid composition of the present invention uses gelatin having suitable freezing power as a freeze-dried scaffold and L-HPC and CMC-Na or crosslinked CMC-Na as a disintegrant, and can impart excellent tablet hardness and disintegratability required for various disintegrating tablets and can obtain excellent formability in preparing tablets, due to their synergistic effects. In particular, a disintegrating solid composition consisting of 220 freezing strength gelatin, L-HPC and CMC-Na has a hardness of more than 4N, preferably more than 7N, more preferably more than 8N; and has a disintegration time in water of 1 to 15 seconds, more preferably 1 to 10 seconds, further preferably 1 to 5 seconds; in addition, the composition has good formability, no breakage and no residue, is suitable for aluminum plastic bubble caps, has good taste and has no irritation to oral mucosa. Therefore, the disintegrable solid composition can be used as a preparation platform to blend a plurality of drug effect ingredients, and finally, the purpose of treating different diseases is achieved.
Detailed Description
The present invention is described in detail by the following examples, which are provided for the purpose of further illustration only and are not to be construed as limiting the scope of the present invention, and the insubstantial modifications and adaptations thereof by those skilled in the art based on the teachings of the present invention are intended to be covered by the present invention.
If the raw materials (including the raw material drugs and the auxiliary materials) and the equipment in the embodiment or the test example without other descriptions are as follows:
1) The raw material medicaments comprise:
Figure BDA0003576866810000131
Figure BDA0003576866810000141
2) Auxiliary materials:
name (R) Batch number Manufacturer of the product
Gelatin 120LB8 (120 jelly) 2782413 ROUSSELOT (GUANGDONG) GELATIN Co.,Ltd.
Gelatin 220LB8 (220 frozen power) 2822835 ROUSSELOT (GUANGDONG) GELATIN Co.,Ltd.
Gelatin 250LB8 (250 frozen power) 2820768 ROUSSELOT (GUANGDONG) GELATIN Co.,Ltd.
Starch (Potato starch) VNL95 GUANGZHOU HONSEA INDUSTRY Co.,Ltd.
CMC-Na 7LF(41mpa.s，0.7) NPE-0017 Shanghai Senjun chemical preparation auxiliary materials Co Ltd
Cross-linked CMC-Na 71119070409 Shanghai hong pharmaceutic adjuvant technology Limited company
L-HPC，SH-LH21 190913 ANHUI SUNHERE PHARMACEUTICAL EXCIPIENTS Co.,Ltd.
Lactose, super Tab14SD 104CWLN DFE pharma
Glycine V019090690 Merck in germany
PEG1000 20200402 NANJING WELL PHARMACEUTICAL Co.,Ltd.
Mannitol, 50C E244J Roguet (Roguet)
3) The instrument comprises the following steps:
name (R) Model number Manufacturer(s) of
Freeze dryer Advantage XL-70 Virtis SP Scientific
Tablet hardness tester YD-2 Tianjin Guoming Medicine Equipment Co.,Ltd.
The detection method comprises the following steps:
hardness was measured by a tablet hardness tester.
The disintegration time is tested according to 0921 disintegration time limit inspection method of the general rule of the Chinese pharmacopoeia 2020 edition.
Appearance and package residue were observed by naked eye.
Example 1
Example 1 provides a disintegrating solid composition A1 having the composition given in table 1a below.
TABLE 1a
Figure BDA0003576866810000142
Figure BDA0003576866810000151
The preparation process comprises the following steps: adding gelatin into 50 ℃ water, stirring until the gelatin is completely dissolved, adding starch, stirring until the starch is completely dissolved, cooling to room temperature, adding other raw materials, stirring until the other raw materials are completely dissolved, dropwise adding 261 mu L of the mixture into an aluminum-plastic bubble cap by using a liquid transfer gun, freeze-drying for 5 hours in a freeze-dryer, taking out, and testing related physical properties, wherein the results are shown in the following table 1b.
The test results are shown in table 1b.
TABLE 1b
Tablet weight Hardness of Disintegration time Appearance of the product Taste of food Packaging residue
38.5mg 4.2N 2s Smooth and flat Has no foreign body sensation Has no residue
Example 2
Example 2 provides a disintegrating solid composition A2, with the composition given in table 2a below.
TABLE 2a
Name of material Quality (g)
Starch 3
Gelatin (220 frozen power) 1
Mannitol 10.5
Lactose 2
PEG1000 0.5
Water (W) 100
The preparation process comprises the following steps: adding gelatin into 50 ℃ water, stirring until the gelatin is completely dissolved, adding starch, stirring until the gelatin is completely dissolved, cooling to room temperature, adding other raw materials, stirring until the other raw materials are completely dissolved, dropwise adding 261 mu L of the mixture into an aluminum-plastic bubble cap by using a liquid transfer gun, freeze-drying for 5 hours in a freeze dryer, taking out, and testing the related physical properties, wherein the results are shown in the following table 2b. The test results are shown in table 2b.
TABLE 2b
Tablet weight Hardness of Disintegration time Appearance of the product Taste of food Packaging residue
37mg 6.3N 1.5s Smooth and flat Has no foreign body sensation Has no residue
Example 3
Example 3 provides a disintegrating solid composition A3, with the composition given in table 3a below.
TABLE 3a
Name of material Quality (g)
Gelatin (220 frozen power) 0.5
Mannitol 13.915
Cross-linked CMC-Na 0.085
Lactose 2
PEG1000 0.5
Water (I) 100
The preparation process comprises the following steps: adding gelatin into 50 ℃ water, stirring until the gelatin is completely dissolved, cooling to room temperature, adding other raw materials, stirring until the gelatin is completely dissolved, dropwise adding 261 mu L of gelatin into the aluminum-plastic bubble cap by using a liquid transfer gun, freeze-drying in a freeze dryer for 5 hours, taking out, and testing related physical properties, wherein the results are shown in the following table 3b.
TABLE 3b
Tablet weight Hardness of Disintegration time Appearance of the product Taste of the product Packing residueRetention of
40mg 3.5N 1s Smooth and flat No foreign body sensation Has no residue
Example 4
Example 4 provides a disintegrating solid composition A4, with the composition given in table 4a below.
TABLE 4a
Name of material Mass (g)
Gelatin (120 frozen power) 1
Mannitol 6.2075
Cross-linked CMC-Na 0.0425
Lactose 1
PEG1000 0.25
Water (W) 50
The preparation process comprises the following steps: adding gelatin into 50 ℃ water, stirring until the gelatin is completely dissolved, cooling to room temperature, adding other raw materials, stirring until the gelatin is completely dissolved, dropwise adding 261 mu L of gelatin into the aluminum-plastic bubble cap by using a liquid transfer gun, freeze-drying in a freeze dryer for 5 hours, taking out, and testing related physical properties, wherein the results are shown in the following table 4.
TABLE 4b
Figure BDA0003576866810000161
Figure BDA0003576866810000171
Example 5
Example 5 provides a disintegrating solid composition A5, with the composition given in table 5a below.
TABLE 5a
Name of material Mass (g)
Gelatin (250 frozen power) 0.5
Mannitol 6.2075
Cross-linked CMC-Na 0.0425
Lactose 1
PEG1000 0.25
Water (I) 50
The preparation process comprises the following steps: adding gelatin into 50 ℃ water, stirring until the gelatin is completely dissolved, cooling to room temperature, adding other raw materials, stirring until the gelatin is completely dissolved, dropwise adding 261 mu L of gelatin into the aluminum-plastic bubble cap by using a liquid transfer gun, freeze-drying in a freeze dryer for 5 hours, taking out, and testing related physical properties, wherein the results are shown in the following table 5b.
TABLE 5b
Tablet weight Hardness of Disintegration time Appearance of the product Taste of the product Packaging residue
40mg 8N 15s Smooth and flat Sense of micro foreign body Has no residue
Example 6
Example 6 provides a disintegrating solid composition A6, with the composition given in table 6a below.
TABLE 6a
Name of material Mass (g)
Gelatin (220 frozen power) 1
Mannitol 12.65
L-HPC 0.85
Lactose 2
PEG1000 0.5
Water (W) 100
The preparation process comprises the following steps: adding gelatin into 50 deg.C water, stirring to dissolve completely, cooling to room temperature, adding other materials, stirring to dissolve completely, adding 261 μ L of gelatin into the aluminum-plastic bubble cap, lyophilizing for 5 hr, taking out, and testing the related physical properties as shown in Table 6b below.
TABLE 6b
Tablet weight Hardness of Disintegration time Appearance of the product Taste of the product Packaging residue
38mg 8.2N 2s Smooth and flat Has foreign body sensation Has no residue
Example 7
Example 7 provides a disintegrating solid composition A7, with the composition given in table 7a below.
TABLE 7a
Name of material Quality (g)
Gelatin (220 frozen power) 0.5
Mannitol 5.825
L-HPC 0.425
Lactose 1
Glycine 0.5
PEG1000 0.25
Water (W) 50
The preparation process comprises the following steps: adding gelatin into 50 deg.C water, stirring to dissolve completely, cooling to room temperature, adding other materials, stirring to dissolve completely, adding 261 μ L of gelatin into the aluminum-plastic bubble cap, lyophilizing for 5 hr, taking out, and testing the related physical properties as shown in Table 7b below.
TABLE 7b
Tablet weight Hardness of Disintegration time Appearance of the product Taste of food Packaging residue
40mg 8.5N 3s Smooth and flat Sense of micro foreign body Has no residue
Example 8
Example 8 provides a disintegrating solid composition A8, with the composition given in table 8a below.
TABLE 8a
Figure BDA0003576866810000181
Figure BDA0003576866810000191
The preparation process comprises the following steps: adding gelatin into 50 ℃ water, stirring until the gelatin is completely dissolved, cooling to room temperature, adding other raw materials, stirring until the gelatin is completely dissolved, dropwise adding 261 mu L of gelatin into the aluminum-plastic bubble cap by using a liquid transfer gun, freeze-drying in a freeze dryer for 5 hours, taking out, and testing related physical properties, wherein the results are shown in the following table 8b.
TABLE 8b
Tablet weight Hardness of Disintegration time Appearance of the product Taste of food Packaging residue
40mg 8.5N 2s Smooth and flat No foreign body sensation Has no residue
Example 9
Example 9 provides a disintegrating solid composition A9, with the composition given in table 9a below.
TABLE 9a
Name of material Mass (g)
Gelatin (220 frozen power) 0.5
Mannitol 6.2875
CMC-Na 0.3083
L-HPC 0.1542
Lactose 1
Glycine 0.25
PEG1000 0.25
Water (W) 50
The preparation process comprises the following steps: adding gelatin into 50 ℃ water, stirring until the gelatin is completely dissolved, cooling to room temperature, adding other raw materials, stirring until the gelatin is completely dissolved, dropwise adding 261 mu L of gelatin into the aluminum-plastic bubble cap by using a liquid transfer gun, freeze-drying in a freeze dryer for 5 hours, taking out, and testing related physical properties, wherein the results are shown in the following table 9b.
TABLE 9b
Tablet weight Hardness of Disintegration time Appearance of the product Taste of food Packaging residue
40mg 9.3N 3s Smooth and flat Has no foreign body sensation Has no residue
Example 10
Example 10 provides a disintegrating solid composition a10, with the composition given in table 10a below.
TABLE 10a
Name of material Quality (g)
Gelatin (220 frozen power) 0.5
Mannitol 6.2875
CMC-Na 0.3469
L-HPC 0.1156
Lactose 1
Glycine 0.25
PEG1000 0.25
Water (I) 50
The preparation process comprises the following steps: adding gelatin into 50 deg.C water, stirring to dissolve completely, cooling to room temperature, adding other materials, stirring to dissolve completely, adding 261 μ L of gelatin into the aluminum-plastic bubble cap, lyophilizing for 5 hr, taking out, and testing the related physical properties as shown in Table 10b below.
TABLE 10b
Tablet weight Hardness of Disintegration time Appearance of the product Taste of the product Packaging residue
40mg 9.1N 3s Smooth and flat Has no foreign body sensation Has no residue
Example 11
Example 11 provides a disintegrating solid composition a11, with the composition given in table 11a below.
TABLE 11a
Figure BDA0003576866810000201
Figure BDA0003576866810000211
The preparation process comprises the following steps: adding gelatin into 50 deg.C water, stirring to dissolve completely, cooling to room temperature, adding other materials, stirring to dissolve completely, adding 261 μ L of gelatin into aluminum plastic bubble cap, lyophilizing for 5 hr, and taking out to test the related physical properties, the results are shown in Table 11b below.
TABLE 11b
Tablet weight Hardness of Disintegration time Appearance of the product Taste of food Packaging residue
40mg 10N 3s Smooth and flat Has no foreign body sensation Has no residue
Example 12
Example 12 provides an orally disintegrating sublingual tablet formulation C1, with the composition given in table 12a below.
TABLE 12a
Name of material Quality (g)
Dexmedetomidine hydrochloride 0.017535
Gelatin (220 frozen power) 0.5
Mannitol 6.2875
CMC-Na 0.25
L-HPC 0.2125
Lactose 1
Glycine 0.25
PEG1000 0.25
Water (W) 50
The preparation process comprises the following steps: adding gelatin into 50 deg.C water, stirring to dissolve completely, cooling to room temperature, adding other materials, stirring to dissolve completely, adding 261 μ L of gelatin into the aluminum-plastic bubble cap, lyophilizing for 5 hr, taking out, and testing the related physical properties as shown in Table 12b below.
TABLE 12b
Tablet weight Hardness of Disintegration time Appearance of the product Taste of food Packaging residue
40mg 9N 3s Smooth and flat / Has no residue
Example 13
Example 13 provides an orally disintegrating sublingual tablet formulation C2, with the composition given in table 13a below.
TABLE 13a
Name of material Quality (g)
Buspirone 0.2245
Gelatin (220 frozen power) 0.5
Mannitol 6.2875
CMC-Na 0.25
L-HPC 0.2125
Lactose 1
Glycine 0.25
PEG1000 0.25
Water (W) 50
The preparation process comprises the following steps: adding gelatin into 50 deg.C water, stirring to dissolve completely, cooling to room temperature, adding other materials, stirring to dissolve completely, adding 261 μ L of each material into aluminum plastic bubble cap, lyophilizing for 5 hr, and taking out to test the related physical properties, the results are shown in Table 13b below.
TABLE 13b
Tablet weight Hardness of Disintegration time Appearance of the product Taste of food Packaging residue
40mg 11N 1s Smooth and flat No foreign body sensation Has no residue
Example 14
Example 14 provides an orally disintegrating sublingual tablet formulation C3, having the composition given in table 14a below.
TABLE 14a
Figure BDA0003576866810000221
Figure BDA0003576866810000231
The preparation process comprises the following steps: adding gelatin into 50 deg.C water, stirring to dissolve completely, cooling to room temperature, adding other materials, stirring to dissolve completely, adding 261 μ L of gelatin into the aluminum-plastic bubble cap, lyophilizing for 5 hr, taking out, and testing the related physical properties as shown in Table 14b below.
TABLE 14b
Tablet weight Hardness of Disintegration time Appearance of the product Taste of food Packaging residue
40mg 10N 3s Smooth and flat No foreign body sensation Has no residue
Example 15
Example 15 provides an orally disintegrating sublingual tablet formulation C4, with the composition given in table 15a below.
TABLE 15a
Name of material Mass (g)
Risperidone 0.2245
Gelatin (220 frozen power) 0.5
Mannitol 6.2875
CMC-Na 0.25
L-HPC 0.2125
Lactose 1
Glycine 0.25
PEG1000 0.25
Water (I) 50
The preparation process comprises the following steps: adding gelatin into 50 deg.C water, stirring to dissolve completely, cooling to room temperature, adding other materials, stirring to dissolve completely, adding 261 μ L of gelatin into the aluminum-plastic bubble cap, lyophilizing for 5 hr, taking out, and testing the related physical properties as shown in Table 15b below.
TABLE 15b
Tablet weight Hardness of Disintegration time Appearance of the product Taste of the product Packaging residue
40mg 11N 2s Smooth and flat Has no foreign body sensation Has no residue
Comparative example 1
Comparative example 1 provides a disintegrating solid composition B1, with the composition given in table 1c below.
TABLE 1c
Name of material Quality (g)
Gelatin (220 frozen power) 0.5
Mannitol 6.2875
Cross-linked CMC-Na 0.1542
L-HPC 0.3083
Lactose 1
Glycine 0.25
PEG1000 0.25
Water (W) 50
The preparation process comprises the following steps: adding gelatin into 50 ℃ water, stirring until the gelatin is completely dissolved, cooling to room temperature, adding other raw materials, stirring until the gelatin is completely dissolved, dropwise adding 261 mu L of gelatin into the aluminum-plastic bubble cap by using a liquid transfer gun, freeze-drying in a freeze dryer for 5 hours, taking out, and testing related physical properties, wherein the results are shown in the following table 1d.
TABLE 1d
Tablet weight Hardness of Disintegration time Appearance of the product Taste of the product Packaging residue
40mg 6.2N 3s Smooth and flat Has no foreign body sensation Small amount of residue
Comparative example 2
Comparative example 2 provides a disintegrating solid composition B2, with the composition given in table 2c below.
TABLE 2c
Name of material Quality (g)
Gelatin (220 frozen power) 0.5
Mannitol 6.2875
Cross-linked CMC-Na 0.3083
L-HPC 0.1542
Lactose 1
Glycine 0.25
PEG1000 0.25
Water (W) 50
The preparation process comprises the following steps: adding gelatin into 50 deg.C water, stirring to dissolve completely, cooling to room temperature, adding other materials, stirring to dissolve completely, adding 261 μ L of gelatin into the aluminum-plastic bubble cap, lyophilizing for 5 hr, taking out, and testing the related physical properties as shown in Table 2d below.
TABLE 2d
Tablet weight Hardness of Disintegration time Appearance of the product Taste of the product Packaging residue
40mg 5.3N 3s Smooth and flat Has no foreign body sensation Small amount of residue
Comparative example 3
Comparative example 3 provides a disintegrating solid composition B3, with the composition given in table 3c below.
TABLE 3c
Name of material Quality (g)
Gelatin (220 frozen power) 0.5
Mannitol 6.2875
Cross-linked CMC-Na 0.1156
L-HPC 0.3469
Lactose 1
Glycine 0.25
PEG1000 0.25
Water (W) 50
The preparation process comprises the following steps: adding gelatin into 50 deg.C water, stirring to dissolve completely, cooling to room temperature, adding other materials, stirring to dissolve completely, adding 261 μ L of gelatin into the aluminum-plastic bubble cap, lyophilizing for 5 hr, taking out, and testing the related physical properties as shown in Table 3d below.
TABLE 3d
Tablet weight Hardness of Disintegration time Appearance of the product Taste of the product Packaging residue
40mg 2.2N 4s Smooth and flat Has no foreign body sensation Severe residue of
Comparative example 4
Comparative example 4 provides a disintegrating solid composition B4, with the composition given in table 4c below.
TABLE 4c
Name of material Quality (g)
Gelatin (220 jelly)Force) 0.5
Mannitol 6.2875
Cross-linked CMC-Na 0.3469
L-HPC 0.1156
Lactose 1
Glycine 0.25
PEG1000 0.25
Water (I) 50
The preparation process comprises the following steps: adding gelatin into 50 deg.C water, stirring to dissolve completely, cooling to room temperature, adding other materials, stirring to dissolve completely, adding 261 μ L of gelatin into the aluminum-plastic bubble cap, lyophilizing for 5 hr, taking out, and testing the related physical properties as shown in Table 4d below.
TABLE 4d
Tablet weight Hardness of Disintegration time Appearance of the product Taste of the product Packaging residue
40mg 1.2N 5s Smooth and flat No foreign body sensation Severe residue of
Comparative example 5
Comparative example 5 provides a disintegrating solid composition B5, with the composition given in table 5c below.
TABLE 5c
Figure BDA0003576866810000261
Figure BDA0003576866810000271
The preparation process comprises the following steps: adding gelatin into 50 deg.C water, stirring to dissolve completely, cooling to room temperature, adding other materials, stirring to dissolve completely, adding 261 μ L of gelatin into the aluminum-plastic bubble cap, lyophilizing for 5 hr, taking out, and testing the related physical properties as shown in Table 5d below.
TABLE 5d
Tablet weight Hardness of Disintegration time Appearance of the product Taste of the product Packaging residue
40mg 10.0N 2s Smooth and flat Has no foreign body sensation Severe residue of
Comparative example 6
Comparative example 6 provides a disintegrating solid composition B6, the composition of which is shown in table 6c below.
TABLE 6c
Name of material Quality (g)
Gelatin (220 frozen power) 0.5
Mannitol 5.9575
CMC-Na 0.5
Cross-linked CMC-Na 0.0425
Lactose 1
Glycine 0.25
PEG1000 0.25
Water (W) 50
The preparation process comprises the following steps: adding gelatin into 50 deg.C water, stirring to dissolve completely, cooling to room temperature, adding other materials, stirring to dissolve completely, adding 261 μ L of gelatin into the aluminum-plastic bubble cap, lyophilizing for 5 hr, taking out, and testing the related physical properties as shown in Table 6d below.
TABLE 6d
Tablet weight Hardness of Disintegration time Appearance of the product Taste of the product Packaging residue
40mg 10.2N 22s Smooth and flat No foreign body sensation Severe residue in the skin
Comparative example 7
Comparative example 7 provides a disintegrating solid composition B7, with the composition given in table 7c below.
TABLE 7c
Name of material Quality (g)
Gelatin (220 frozen power) 0.5
Mannitol 6.2875
CMC-Na 0.1542
L-HPC 0.3083
Lactose 1
Glycine 0.25
PEG1000 0.25
Water (I) 50
The preparation process comprises the following steps: adding gelatin into 50 ℃ water, stirring until the gelatin is completely dissolved, cooling to room temperature, adding other raw materials, stirring until the gelatin is completely dissolved, dropwise adding 261 mu L of gelatin into the aluminum-plastic bubble cap by using a liquid transfer gun, freeze-drying in a freeze dryer for 5 hours, taking out, and testing related physical properties, wherein the results are shown in the following table 7d.
TABLE 7d
Tablet weight Hardness of Disintegration time Appearance of the product Taste of the product Packaging residue
40mg 13.4N 2s Smooth and flat No foreign body sensation Small amount of residue
Comparative example 8
Comparative example 8 provides a disintegrating solid composition B8, with the composition given in table 8c below.
TABLE 8c
Figure BDA0003576866810000281
Figure BDA0003576866810000291
The preparation process comprises the following steps: adding gelatin into 50 deg.C water, stirring to dissolve completely, cooling to room temperature, adding other materials, stirring to dissolve completely, adding 261 μ L of gelatin into the aluminum-plastic bubble cap, lyophilizing for 5 hr, taking out, and testing the related physical properties as shown in Table 8d below.
TABLE 8d
Tablet weight Hardness of Disintegration time Appearance of the product Taste of the product Packaging residue
40mg 6.8N 5s Smooth and flat Has no foreign body sensation Small amount of residue
Comparative example 9
Comparative example 9 provides a disintegrating solid composition B9, with the composition given in table 9c below.
TABLE 9c
Name of material Mass (g)
Gelatin (220 frozen power) 0.5
Mannitol 6.2875
CMC-Na(7HF PH；1914mpa.s) 0.25
L-HPC 0.2125
Lactose 1
Glycine 0.25
PEG1000 0.25
Water (W) 50
The preparation process comprises the following steps: adding gelatin into 50 deg.C water, stirring to dissolve completely, cooling to room temperature, adding other materials, stirring to dissolve completely, adding 261 μ L of gelatin into the aluminum-plastic bubble cap, lyophilizing for 5 hr, taking out, and testing the related physical properties as shown in Table 9d below.
TABLE 9d
Tablet weight Hardness of Disintegration time Appearance of the product Taste of food Packaging residue
40mg 5N 5s Smooth and flat Has no foreign body sensation Has no residue
The above embodiments are only examples of the present invention, and are not intended to limit the present invention in other forms, and any person skilled in the art may modify or change the technical content of the above disclosed embodiments to equivalent embodiments with equivalent changes, but all those modifications, equivalents and changes made to the above embodiments according to the technical spirit of the present invention are still within the scope of the present invention.

Claims (13)

1. A disintegrating solid composition comprising (a) a hydrocolloid having a freezing point of 120 bloom or higher, wherein the hydrocolloid is at least one member selected from the group consisting of starch, gelatin, donkey-hide gelatin, deer-horn gelatin and peach gum, and the hydrocolloid accounts for 1 to 25%, preferably 2 to 15%, more preferably 3 to 12% of the total mass of the solid composition.
2. Disintegrating solid composition according to claim 1, wherein the hydrophilic colloid is gelatin and/or starch; preferably the gelatine has a motility of 220 or more bloom, more preferably 220 to 250 bloom.
3. The disintegrating solid composition according to claim 1, further comprising a disintegrant selected from at least one selected from the group consisting of microcrystalline cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, sodium croscarmellose, and crospovidone; preferably, the disintegrant is one or more of low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose and croscarmellose sodium.
4. The disintegrating solid composition according to any one of claims 1 to 2, comprising gelatin and a disintegrating agent, wherein the mass ratio of the gelatin to the disintegrating agent is (1-5): 1, preferably (1-2): 1; the gelatin content accounts for 3-12%, preferably 5-7% of the total mass of the solid composition;
preferably, the disintegrant is low-substituted hydroxypropyl cellulose or a combination of (b 1) sodium carboxymethyl cellulose and/or croscarmellose sodium, and (b 2) low-substituted hydroxypropyl cellulose, and (b 1): (b2) The mass ratio of (b) is (0.6 to 5): 1, preferably (0.7 to 3): 1, and more preferably (1 to 3): 1.
5. The disintegrating solid composition according to any one of claims 1 to 2, comprising gelatin and a disintegrant, wherein the disintegrant is croscarmellose sodium; the mass ratio of the gelatin to the disintegrating agent is (5-25) to 1, preferably (12-23) to 1; the gelatin content accounts for 3-12% of the total mass of the solid composition;
more preferably, the freezing force of the gelatin is 120 bloom, the mass ratio of the gelatin to the croscarmellose sodium is (20-25): 1, preferably (23-24): 1, and the gelatin content accounts for 10-12% of the total mass of the solid composition;
more preferably, the freezing force of the gelatin is 220-250 Brumk, the mass ratio of the gelatin to the croscarmellose sodium is (5-13): 1, preferably (12-13): 1, and the gelatin content accounts for 3-7%, preferably 5-7% of the total mass of the solid composition.
6. The disintegrating solid composition according to any one of claims 1 to 2, comprising gelatin and a disintegrant, wherein the disintegrant is a combination of (b 1) sodium carboxymethylcellulose and (b 2) low-substituted hydroxypropylcellulose, and the ratio of (b 1): (b2) The mass ratio of the gelatin to the disintegrating agent is (1-2) to 1; the gelatin content accounts for 5-7% of the total mass of the solid composition.
7. The disintegrating solid composition according to any one of claims 1 to 6, further comprising at least one of a filler, a lubricant, and a protective agent;
preferably, the mass of the filler accounts for 70 to 98 percent of the total mass of the solid composition, more preferably 80 to 95 percent;
preferably, the lubricant is present in an amount of 0.0001% to 5%, more preferably 0.1% to 5%, by mass based on the total mass of the solid composition;
preferably, the mass of the protective agent is 0.001% to 8%, more preferably 0.5% to 8%, of the total mass of the solid composition.
8. The disintegrating solid composition according to claim 7, wherein the bulking agent comprises at least one of mannitol, erythritol, xylitol, trehalose, lactose, maltose, maltitol, glucose, sucrose, fructose, sorbitol;
preferably, the filler is one or more of mannitol, erythritol, xylitol, trehalose or lactose;
more preferably, the filler is mannitol and lactose, wherein the mass ratio of the lactose to the mannitol is 1 (4-10), preferably 1 (4-8), more preferably 1 (5.5-6.5);
the lubricant comprises at least one of magnesium stearate, silicon dioxide, talc, polyethylene glycol, stearic acid, preferably polyethylene glycol 1000 or polyethylene glycol 2000;
the protective agent comprises at least one of amino acids of glycine, alanine, valine, leucine, isoleucine, serine, threonine, aspartic acid, glutamic acid, asparagine, glutamine, lysine, arginine, cysteine, methionine, phenylalanine, histidine, tryptophan or proline, or salts thereof, preferably glycine, lysine, arginine or histidine.
9. An orally disintegrating solid preparation comprising a biologically active ingredient and the disintegrating solid composition according to any one of claims 1 to 8, wherein the biologically active ingredient is present in an amount of 50% or less, preferably 20% or less, for example 2 to 20%, or 0.2 to 2.5% by weight of the solid preparation;
preferably, the bioactive component is a drug effect component; further preferably, the bioactive ingredient is a central nervous system drug; <xnotran> , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , . </xnotran>
10. The orally disintegrating solid formulation according to claim 9, wherein the dosage form, once placed in the oral cavity, dissolves in a time period of less than 15 seconds, preferably less than 10 seconds, or less than 5 seconds, or less than 2 seconds.
11. The orally disintegrating solid dosage form according to claim 9, wherein the dosage form hardness is 3N or more, preferably 4N or more, or 7N or more, or 8N or more, and most preferably 8 to 9N.
12. The orally disintegrating solid preparation according to any one of claims 8 to 11, wherein the solid preparation is any one of a sublingual tablet, a chewable tablet, a fudge, an oral patch, an oral adhesive tablet, and an oral film.
13. A method for producing the disintegrating solid composition according to any one of claims 1 to 8 or the orally disintegrating solid preparation according to any one of claims 9 to 11, comprising: adding the hydrophilic colloid into a solvent with the temperature of 30-60 ℃, stirring and dissolving completely, cooling to room temperature, optionally adding a disintegrating agent, a filling agent, a lubricating agent, a protective agent and biological activity, stirring uniformly, sampling, injecting into an aluminum-plastic bubble cap, and processing by adopting a thermal processing or solvent evaporation or sublimation mode to obtain the hydrophilic colloid.
CN202210346999.XA 2021-04-07 2022-04-01 Disintegrable solid composition and orally disintegrable solid preparation Pending CN115192723A (en)

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