Disintegrating solid compositions and oral disintegrating solid formulations

Abstract

The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to a disintegrating solid composition and an oral disintegrating solid preparation. The disintegrating solid composition comprises a hydrophilic colloid, and the gel strength of the hydrophilic colloid is above 120 gel force, preferably further comprising a disintegrating agent, particularly L-HPC and CMC-Na or crosslinked CMC-Na as the disintegrating agent. The disintegrating solid composition provided by the present application uses gelatin with suitable gel force as a freeze-drying support, and L-HPC and CMC-Na or crosslinked CMC-Na as the disintegrating agent. Due to the synergistic effect, the disintegrating solid composition can impart excellent tablet hardness and disintegrating property required by various disintegrating tablets, and excellent formability can be obtained when the tablets are prepared.

Description

[0001] This application claims priority to the earlier patent applications filed with the China National Intellectual Property Administration on April 7, 2021 and May 10, 2021, respectively, with patent application numbers CN202110374537.4 and CN202110503420.1, both entitled "Disintegrating Compositions and Orally Disintegrating Solid Dosage Forms". The entire contents of the earlier applications are incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of pharmaceutical formulation technology, and more specifically, this invention relates to disintegrating solid compositions and orally disintegrating solid dosage forms. Background Technology

[0003] Disintegrating tablets readily disintegrate in the body (e.g., in the mouth) after administration. If orally disintegrating tablets are administered orally, disintegration in the mouth without chewing is generally expected to be within 1–30 seconds. Orally disintegrating tablets are highly valuable to users, especially those with poor swallowing abilities, such as infants and the elderly, because they can be taken without water.

[0004] For these types of tablets, there is a need for a formulation that maintains its shape during handling and minimizes pulverization and breakage. Therefore, one aspect of pharmaceutical research on tablets is the need to increase hardness. However, simply providing high hardness is insufficient to achieve the intended purpose as a pharmaceutical formulation, as it can lead to degradation or denaturation of the active ingredient, or alteration of the function of functional particles. While pursuing high hardness through high-pressure compression molding typically increases hardness, there are actually many inconveniences in manufacturing pharmaceutical formulations due to the increased compression molding pressure. For example, many physiologically active ingredients are known to lose their activity when subjected to high-pressure compression molding.

[0005] Therefore, the development of tablets requires ensuring that the tablet itself has sufficient hardness to prevent functional changes in the functional particles due to compression. Additionally, it needs to have an appropriate oral disintegration time. Furthermore, for orally disintegrating tablets, it is also necessary to consider whether there is a noticeable foreign body sensation in the mouth, etc. Summary of the Invention

[0006] The purpose of this invention is to provide a disintegrating solid composition, particularly an oral disintegrating solid dosage form, that combines high hardness and low disintegration time with good clinical application prospects.

[0007] On one hand, the present invention provides a disintegrating solid composition, characterized in that it comprises (a) a hydrophilic colloid with a gel strength of 120 brunc or more, said hydrophilic colloid being selected from at least one of starch, gelatin, donkey-hide gelatin, deer antler glue, and peach gum, and the hydrophilic colloid accounts for 1 to 25% of the total mass of the solid composition, for example 1 to 20%, preferably 2% to 15%, more preferably 3% to 12%.

[0008] More preferably, the hydrophilic colloid is gelatin and / or starch; preferably, the gelatin has a power of 220 or more lumps, more preferably 220 to 250 lumps.

[0009] In a preferred embodiment, the disintegrating solid composition of the present invention further includes a disintegrant selected from at least one of microcrystalline cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium, and croscarmellose; preferably, the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose (L-HPC), sodium carboxymethyl cellulose (CMC-Na), and croscarmellose sodium.

[0010] In a preferred embodiment of the present invention, the disintegrating solid composition comprises gelatin and a disintegrant, wherein the mass ratio of the gelatin to the disintegrant is (1-5):1, preferably (1-2):1; and the gelatin content accounts for 3%-12% of the total mass of the solid composition, preferably 5%-7%.

[0011] More preferably, the disintegrant is a low-substituted hydroxypropyl cellulose or a combination of (b1) sodium carboxymethyl cellulose and / or cross-linked sodium carboxymethyl cellulose and (b2) low-substituted hydroxypropyl cellulose, and the mass ratio of (b1):(b2) is (0.6-5):1, preferably (0.7-3):1, more preferably (1-3):1.

[0012] In a preferred embodiment of the present invention, the disintegrating solid composition comprises gelatin and a disintegrant, wherein the disintegrant is croscarmellose sodium; the mass ratio of the gelatin to the disintegrant is (5-25):1, preferably (12-23):1; and the gelatin content accounts for 3%-12% of the total mass of the solid composition.

[0013] More preferably, when the gelatin gel strength is 120 brunc, the mass ratio of the gelatin to crosslinked sodium carboxymethyl cellulose is (20-25):1, preferably (23-24):1, and the gelatin content accounts for 10%-12% of the total mass of the solid composition.

[0014] More preferably, when the gelatin gel strength is 220-250 brunc, the mass ratio of the gelatin to crosslinked sodium carboxymethyl cellulose is (5-13):1, preferably (12-13):1, and the gelatin content accounts for 3%-7% of the total mass of the solid composition, preferably 5%-7%, for example 5.6%, 5.7%, 5.8% or 5.9%, etc.

[0015] In another preferred embodiment of the invention, the disintegrating solid composition comprises gelatin and a disintegrant. The disintegrant is a combination of (b1) sodium carboxymethyl cellulose and (b2) low-substituted hydroxypropyl cellulose, and the mass ratio of (b1):(b2) is (1-3):1; the mass ratio of gelatin to disintegrant is (1-2):1; and the gelatin content accounts for 5%-7% of the total mass of the solid composition.

[0016] In one embodiment of the invention, the disintegrating solid composition further comprises at least one of a filler, a lubricant, and a protective agent.

[0017] When the disintegrating solid composition of the present invention further comprises a filler, the filler typically accounts for 70-98% of the total mass of the solid composition, preferably 80-95%, and more preferably 80-90%. The filler comprises at least one selected from 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 mannitol and lactose can be mixed in any proportion, preferably with a mass ratio of lactose to mannitol of 1:(4-10), preferably 1:(4-8), and more preferably 1:(5.5-6.5).

[0018] 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% to 95% of the total mass of the solid composition, and wherein the mass ratio of lactose to mannitol is 1:(4 to 8), preferably 1:(5.5 to 6.5).

[0019] When the disintegrating solid composition of the present invention further comprises a lubricant, the mass of the lubricant accounts for 0.0001% to 5% of the total mass of the solid composition, more preferably 0.1% to 5%, and particularly preferably 2% to 3%. The lubricant comprises at least one of magnesium stearate, silica, talc, polyethylene glycol (PEG), and stearic acid, preferably polyethylene glycol, and particularly preferably PEG1000, PEG2000, etc.

[0020] Therefore, in a preferred embodiment of the present invention, the disintegrating solid composition further comprises PEG1000, wherein the content of PEG1000 accounts for 0.1% to 5% of the total mass of the solid composition, preferably 2% to 3%.

[0021] When the disintegrating solid composition of the present invention further contains a protective agent, the mass of the protective agent accounts for 0.001% to 8% of the total mass of the solid composition, more preferably 0.5% to 8%; the protective agent contains at least one of the following amino acids or salts: glycine, alanine, valine, leucine, isoleucine, serine, threonine, aspartic acid, glutamic acid, asparagine, glutamine, lysine, arginine, cysteine, methionine, phenylalanine, histidine, tryptophan or proline, preferably glycine, lysine, arginine or histidine.

[0022] Therefore, in a preferred embodiment of the present invention, the disintegrating solid composition further comprises glycine, wherein the content of glycine accounts for 0.5% to 8% of the total mass of the solid composition, preferably 2% to 6%.

[0023] In a preferred embodiment, the present invention provides a disintegrating solid composition comprising 5%–7% gelatin, a disintegrant, 80%–95% filler, and 2%–3% lubricant, wherein the mass ratio of gelatin to disintegrant is (1–2):1; the lubricant is PEG1000, the filler is mannitol and lactose, the mass ratio of mannitol to lactose is 1:(5.5–6.5), the disintegrant is L-HPC, and the gelatin has a gel strength of 220–250; optionally, it further comprises 5%–8% glycine.

[0024] In a preferred embodiment, the present invention provides a disintegrating solid composition comprising 5%–7% gelatin, a disintegrant, 80%–95% filler, and 2%–3% lubricant, wherein the mass ratio of gelatin to disintegrant is (1–2):1; wherein the lubricant is PEG1000, the filler is mannitol and lactose, the mass ratio of mannitol to lactose is 1:(5.5–6.5), the disintegrant is L-HPC and CMC-Na, wherein the ratio of CMC-Na to L-HPC is (1–3):1, preferably (1.2–1.5):1, and the gelatin has a gel strength of 220–250; optionally, it further comprises 5%–8% glycine.

[0025] In a preferred embodiment, the present invention provides a disintegrating solid composition comprising 10%–12% gelatin, a disintegrant, 80%–95% filler, and 2%–3% lubricant, wherein the mass ratio of gelatin to disintegrant is (23–24):1; wherein the lubricant is PEG1000, the filler is mannitol and lactose, the mass ratio of mannitol to lactose is 1:(5.5–6.5), the disintegrant is CMC-Na or cross-linked CMC-Na, and the gelatin has a gel strength of 120; optionally, it further comprises 5%–8% glycine.

[0026] In a preferred embodiment, the present invention provides a disintegrating solid composition comprising 3%–7% gelatin, a disintegrant, 80%–95% filler, and 2%–3% lubricant, wherein the mass ratio of gelatin to disintegrant is (12–13):1; wherein the lubricant is PEG1000, the filler is mannitol and lactose, the mass ratio of mannitol to lactose is 1:(5.5–6.5), the disintegrant is CMC-Na or cross-linked CMC-Na, and the gelatin has a gel strength of 220–250; optionally, it further comprises 5%–8% glycine.

[0027] In another aspect of the invention, an orally disintegrating solid dosage form is also provided, comprising a bioactive ingredient and the disintegrating solid composition of the present invention, wherein the content of the bioactive ingredient is less than 50% by weight of the solid dosage form, preferably less than 20%, for example 2 to 20%, or 0.2% to 2.5%.

[0028] Preferably, the bioactive ingredient is a pharmacologically active ingredient; more preferably, the bioactive ingredient is a central nervous system drug; even more preferably, the bioactive ingredient is selected from dexmedetomidine, citalopram, excitabine oxalate, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine, duloxetine, camel pinephenanthrene, isoproterenol, isocarboxamide, nicotinamide, phenelzine, phenelzine, selegiline, toloxacin, tranylcypromine, bromofaradamine, moclobemide, amitriptyline, amoxapine, bupirocin, clomipramine, desipramine, diphenhydramine, duthiramine, doxepin, propylmiramine, eplelide, lofepramine, melitral, nortriptyline, opiramol, protriptyline, trimelamin, maprotiline. Mianserin, Nefazodone, Trazodone, Lithium Orotate, Sodium Valproate, Sodium Valproate, Lamotrigine, Carbamazepine, Gabapentin, Oxcarbazepine, Topiramate, Haloperidol, Chlorpromazine, Fluphenazine, Perphenazine, Prochlorperazine, Thiorpyridazine, Trifluoperazine, Metamethazine, Promethazine, Triflupromazine, Levoprozine, Promethazine, Chlorprothiazide, Dapsone, Bezothiazide, Clozapine, Olanzapine, Risperidone, Buspirone, Quetiapine, Amisulpride, Palpanridone, Dopamine, Biphenylrutin, Norclozapine, Aripiprazole, Butenaazine, Cannabidiol, Fluperidone, Loxapine, Mesodazine, Morindaone, Pimozide, Prochlorperazine, Thioridazine, Tevothiazide, Trifluoperazine, Quetiapine, or Ziprasidone.

[0029] In a preferred embodiment of the invention, the orally disintegrating solid preparation, once placed in the oral cavity, dissolves within a time period of less than 15 seconds, preferably less than 10 seconds, or less than 5 seconds, or less than 2 seconds.

[0030] In a preferred embodiment of the present invention, the oral disintegrating solid dosage form has a hardness of 3N or greater, preferably 4N or greater, or 7N or greater, or 8N or greater, and most preferably 8 to 9N.

[0031] Particularly preferred is that the oral disintegrating solid dosage form dissolves in less than 5 seconds once placed in the oral cavity, and the dosage form hardness is 8-9 N.

[0032] The orally disintegrating solid dosage form provided by this invention can be any one of sublingual tablets, chewable tablets, tablets, oral patches, oral adhesive tablets, or oral films.

[0033] In another aspect of the present invention, a method for preparing the disintegrating solid composition or the oral disintegrating solid formulation is also provided, comprising adding a hydrophilic colloid to a solvent at 30-60°C, stirring until completely dissolved, cooling to room temperature, optionally adding a disintegrant, filler, lubricant, protectant, and bioactive ingredient, stirring until homogeneous, taking a sample and injecting it into an aluminum-plastic blister pack, and processing it by heat treatment, solvent evaporation, or sublimation.

[0034] Unless otherwise stated, implied from the context, or as is customary in the art, all parts and percentages in this application are based on weight, and the testing and characterization methods used are concurrent with the filing date of this application. If any definition of a specific term disclosed in the prior art is inconsistent with any definition provided in this application, the definition provided in this application shall prevail.

[0035] The terms "preferred," "more preferably," and "more suitable" used in this invention refer to embodiments of the invention that provide certain beneficial effects under certain circumstances. However, other embodiments may also be preferred under the same or other circumstances. Furthermore, the description of one or more preferred embodiments does not imply that other embodiments are unavailable, nor is it intended to exclude other embodiments from the scope of this invention. All components not mentioned in this invention are commercially available.

[0036] Unless otherwise stated, the excipients mentioned in this invention, such as fillers, disintegrants, lubricants, protectants, and hydrogels, are all pharmaceutical excipients, and their meanings are consistent with the conventional meanings in the field, such as the interpretations of terms in pharmacopoeias or pharmaceutical excipient manuals.

[0037] The "total mass of solid composition" mentioned in this invention refers to the total mass of excipients and bioactive components in the disintegrating solid composition, that is, the dry weight after removing the solvent (such as water).

[0038] After careful research, the inventors discovered that by combining a hydrophilic colloid with a certain gel strength with an optimized disintegrant, especially when the disintegrant is selected to include L-HPC and CMC-Na, the synergistic effect of the three results in a finished product that does not pulverize, break, or leave residue, achieves a hardness of 8-9 N, has a disintegration time of about 2 seconds, and also has a good taste, thus avoiding the deactivation of the active pharmaceutical ingredients.

[0039] After in-depth research, the inventors considered the gritty feeling caused by the insolubility of microcrystalline cellulose and its susceptibility to the physical properties of pharmaceutical ingredients, which could significantly impact drug disintegration. Therefore, in an attempt to use a microcrystalline cellulose-free solution, starch was used as a substitute. However, it was known that excessive starch content negatively affected the compressibility of the tablets. In subsequent research, the inventors unexpectedly discovered that even without starch, the desired disintegration properties could be achieved using specific gelatin formulations. However, balancing the hardness of solid dosage forms was difficult. Further research, when combined with a disintegrant of a specific composition, unexpectedly yielded a disintegrant composition that combined high hardness, suitable disintegration time, and excellent appearance quality, and could serve as a formulation platform compatible with various pharmaceutical ingredients.

[0040] The first aspect of the present invention provides a disintegrating solid composition comprising (a) a hydrocolloid with a gel strength of 120 Brønsted or more, (b) a disintegrant, and (c) a filler; wherein the hydrocolloid is selected from at least one of starch, gelatin, donkey-hide gelatin, deer antler glue, and peach gum, and the hydrocolloid accounts for 1 to 20% of the total mass of the composition.

[0041] <(a) Hydrocolloids with a freezing power of 120 Brønsted>

[0042] Hydrocolloids are colloidal substances that have a strong affinity for water. Examples of such substances include animal glue, starch, gum, and protein. Examples of animal glues include gelatin, donkey-hide gelatin, and deer antler glue, while examples of gums include peach gum, konjac gum, and carrageenan.

[0043] The hydrocolloid suitable for use in this invention is preferably at least one of starch, gelatin, donkey-hide gelatin, deer antler glue, and peach gum. The amount of the hydrocolloid used is preferably 1-20 wt% of the total mass of the composition, more preferably 2-10%, further preferably 2-8%, and even more preferably 5-8%. When the above-preferred hydrocolloids are used in combination, the total amount of the mixture is generally maintained the same as when used individually, and the mixing ratio of each can be arbitrary. Through research, gelatin and / or starch are found to be the most suitable hydrocolloids for this invention, wherein the gelatin used is an amphoteric electrolyte that can act as a freeze-drying scaffold to coagulate charged particles into clumps.

[0044] In further research on gelatin, the inventors unexpectedly discovered that by selecting gelatin with different gel strengths, tablets with suitable disintegration times and varying hardness could be obtained. Preferably, the gel strength of the gelatin is between 100 and 250 brangrams, more preferably between 120 and 225 brangrams, including, for example, 150, 160, 180, 200, 220, and 250 brangrams; among these, a gel strength of 220 brangrams is more preferred.

[0045] Here, "freezing power" refers to the freezing capacity of a solution. It is the force applied when the probe of a freezing power testing instrument, after the solution has dissolved and condensed for a certain period in a dedicated freezing power test bottle under specified testing conditions, forms a cylinder with a diameter of 12.7 mm. This force is measured in Blohmgrams (12.7 mm) when pressed 4 mm into the surface of the gel containing 6.67% or 12.5% ​​gelatin. In one embodiment, a mixture of gelatin and starch is used as a hydrophilic colloid. Studies have found that even by combining gelatin with starch of different freezing powers, it is difficult to obtain tablets with high hardness. This is because the water insolubility of starch was considered in the experiments. While maintaining good taste, it was not possible to achieve better synergy between the starch and gelatin by improving the starch quality. This is a common problem in starch-containing oral tablets. Furthermore, the freeze-drying process results in poor starch formability; higher starch content can cause tablet cracking or breakage.

[0046] Further research revealed that in embodiments that do not contain starch as a hydrophilic colloid, different adjustments to the disintegrant not only fundamentally affect the disintegration time, but also the hardness and residue level.

[0047] <(b) Disintegrants>

[0048] Disintegrants are substances that cause tablets to rapidly break down into small particles upon contact with a liquid. These substances generally have excellent water absorption and swelling properties, thereby achieving tablet disintegration.

[0049] For the disintegrants in this invention, research has shown that preferred disintegrants include at least one selected from microcrystalline cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium, and croscarmellose. More preferred disintegrants include low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium, and croscarmellose. These preferred disintegrants can be used alone or in combination. When used alone, their dosage is 0.5-15% of the total mass of the composition, such as 3%-12%, 1-10%, preferably 3-6% or 5%-7%. Excessive use of these disintegrants can cause tablet swelling, forming a water-blocking layer and affecting disintegrant properties. When multiple preferred disintegrants are used in combination, the total dosage of the mixture is generally maintained as when used alone, and the mixing ratio of each can be arbitrary.

[0050] In a preferred embodiment, the disintegrant comprises (b1) sodium carboxymethyl cellulose and / or croscarmellose sodium carboxymethyl cellulose; and (b2) low-substituted hydroxypropyl cellulose. More preferably, especially when the disintegrant is (b1) sodium carboxymethyl cellulose and (b2) low-substituted hydroxypropyl cellulose, the overall performance is best when the mass ratio of (b1):(b2) is (0.6–5):1, more preferably (0.7–3):1, even more preferably (1–3):1, and even more preferably (1–2):1.

[0051] Compared to microcrystalline cellulose or sodium carboxymethyl cellulose alone as a disintegrant, the preferred disintegrants are (b1) sodium carboxymethyl cellulose and (b2) low-substituted hydroxypropyl cellulose.

[0052] Sodium carboxymethyl cellulose is typically classified into four types based on its viscosity: ultra-high viscosity, high viscosity, medium viscosity, and low viscosity. Generally, the lower the viscosity, the smaller the molecular weight and the lower the degree of substitution.

[0053] Unexpectedly, it was found that sodium carboxymethyl cellulose and gelatin with different degrees of substitution exhibit different properties in this system, such as their effects on taste and residue. It is speculated that sodium carboxymethyl cellulose with an appropriate degree of substitution can make the distribution of water in the network structure of gelatin and fillers more uniform, resulting in smaller ice crystals formed during freeze-drying and condensation, and less damage to the microstructure of tablets. Conversely, if the degree of substitution is too low, poor water solubility will lead to poor taste of the tablets.

[0054] Considering the final overall performance of the tablets, the degree of substitution of sodium carboxymethyl cellulose in this invention is between 0.5 and 2.5, preferably 0.6 to 1.2, more preferably 0.65 to 0.85, and most preferably 0.7. The viscosity is 25 to 1500 mPa·s, more preferably 25 to 1000 mPa·s, and even more preferably 25 to 800 mPa·s. For example, the viscosity is preferably any value among 25, 50, 100, 200, 300, 400, 500, 600, 700, and 800, or any value within a range starting and ending at any two of these values.

[0055] Sodium carboxymethyl cellulose with a substitution degree between 0.6 and 0.9 as described above can be obtained commercially, such as including but not limited to 7HF4XF PH, 7HF PH, 7H3SF PH, 7HOF PH, 7M31F PH, 7MF PH, 7M8SF PH, 7M1FPH, 7LF PH, 7L2P, etc.

[0056] The degree of substitution of sodium carboxymethyl cellulose refers to the average number of hydroxyl groups on each glucose unit that are replaced by ether groups, with a theoretical maximum degree of substitution of 3. The viscosity of sodium carboxymethyl cellulose is short for dynamic viscosity, and its unit is Pas or millipas (mPa·s). It refers to the viscosity of a 2% sodium carboxymethyl cellulose aqueous solution measured at 25℃±0.2℃.

[0057] In this study, sodium carboxymethyl cellulose partially neutralizes the gelatin molecules with 220% gluten strength, reducing intermolecular repulsion and resulting in incomplete molecular chain unfolding. Meanwhile, low-substituted hydroxypropyl cellulose competes for cross-linking bonds between gelatin molecules through cross-linking bonds, thus synergistically promoting disintegration and increasing hardness with specific gelatin. The results show that the optimal mass ratio of sodium carboxymethyl cellulose (b1) with suitable substitution degree and viscosity and low-substituted hydroxypropyl cellulose (b2) is (0.7–3):1, resulting in excellent hardness, disintegration time, and taste. Surprisingly, the composition obtained by the disintegrant at this ratio leaves almost no residue on aluminum-plastic blister packs after peeling, making it very suitable for the freeze-drying process to produce disintegrating tablets.

[0058] <(c) Filler>

[0059] Fillers are substances that are typically used to fill the weight or volume of tablets to facilitate tablet forming. Examples include sugars or sugar alcohols such as lactose, sucrose, fructose, dextran glucose, mannitol, xylitol, erythritol, sorbitol, and maltitol; cellulose derivatives such as microcrystalline cellulose and lignocellulose; and starches such as starch, pregelatinized starch, corn starch, and modified corn starch.

[0060] The fillers suitable for this invention are preferably sugar or sugar alcohol compounds, such as mannitol, erythritol, xylitol, trehalose, lactose, maltose, maltitol, glucose, sucrose, fructose, mannitol, and sorbitol, with mannitol, erythritol, xylitol, trehalose, and lactose being more preferred. These fillers can be used alone or in mixtures of two or more, preferably comprising 70-98% of the total mass of the composition, more preferably 80-95%, and even more preferably 80-90%. When multiple preferred fillers are used in combination, the total amount of the mixture is generally maintained as when used alone, and the mixing ratio of each filler can be arbitrary. In one embodiment, the fillers are lactose and mannitol, wherein the mass ratio of lactose to mannitol is 1:(4-10), preferably 1:(4-8), and more preferably 1:(5.5-6.5).

[0061] In the system, gelatin with appropriate freezing power reacts with disintegrants to form a composite system, which encapsulates the filler and plays a supporting role in the network structure.

[0062] The amount of each component in the disintegrating solid composition of the present invention described above is appropriately determined according to the type of each component, the type of application, and the intended use. Preferably, it comprises 1 to 20% (a) a hydrophilic colloid with a gel strength of 120 blumk or more, 0.5 to 15% (b) a disintegrant, and 70 to 98% (c) a filler, based on a percentage of the total weight of the disintegrating solid composition; more preferably, it comprises 2 to 10% (a) a hydrophilic colloid with a gel strength of 120 blumk or more, 1 to 10% (b) a disintegrant, and 80 to 95% (c) a filler.

[0063] Furthermore, in addition to the above-mentioned (a) hydrophilic colloid with a freezing power of 120 Brønsted or more, (b) disintegrant, and (c) filler, the disintegrating solid composition of the present invention may also contain at least one additive selected from lubricants and protectants known to those skilled in the art.

[0064] As a lubricant, the present invention does not particularly limit its use and it can be any lubricant conventionally used in the art, preferably magnesium stearate, silica, talc, polyethylene glycol, or stearic acid. These preferred lubricants can significantly increase the flowability between particles in the composition and improve the filler condition. Polyethylene glycol is more preferred, including but not limited to PEG100, PEG200, PEG400, PEG800, PEG1000, PEG1500, PEG2000, and PEG4000, with PEG1000 being the most preferred. In the compositions of the present invention, these lubricants can be used alone or in combination of multiple types. The content of the lubricant in the composition is not limited and can be 0 to 5% (w / w) of the total mass of the composition, preferably 0.1 to 5% (w / w), more preferably 1 to 5% (w / w).

[0065] As a protective agent, the present invention does not have any particular limitation, and it can be any protective agent conventionally used in the art, preferably 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 or their salts, or peptides, proteins, and other amino acids and their derivatives containing these amino acids as constituent amino acids, more preferably glycine, lysine, arginine, or histidine. In the compositions of the present invention, these protective agents can be used alone or in combination of multiple types, preferably glycine; the content of the protective agent in the composition is not limited, and can be 0 to 8% (w / w) of the total mass of the composition, preferably 0.5 to 8% (w / w), more preferably 2 to 8% (w / w).

[0066] When the disintegrating solids composition of the present invention contains, in addition to the above-mentioned (a) hydrophilic colloid with a freezing power of 120 Brumg or more, (b) disintegrant, and (c) filler, at least one additive selected from lubricants and protectants, it is preferable that, by percentage of the total weight of the disintegrating solids composition, it includes 1 to 20% of (a) hydrophilic colloid with a freezing power of 120 Brumg or more, 0.5 to 15% of (b) disintegrant, 70 to 98% of (c) filler, 0 to 5% of lubricant, and 0 to 8% of protectant.

[0067] More preferably, it includes 1 to 20% of (a) a hydrophilic colloid with a freezing power of 120 Brønsted or more, 0.5 to 15% of (b) a disintegrant, 80 to 95% of (c) a filler, 0.1 to 5% of a lubricant and 0.5 to 8% of a protectant.

[0068] More preferably, it includes 2 to 10% of (a) a hydrophilic colloid with a freezing power of 120 Brønsted or more, 1 to 10% of (b) a disintegrant, 80 to 95% of (c) a filler, 0.1 to 5% of a lubricant and 0.5 to 8% of a protectant.

[0069] More preferably, it includes 2-8% of (a) a hydrophilic colloid with a freezing power of 120 Brønsted or more, 3-6% of (b) a disintegrant, 80-90% of (c) a filler, 0.1-5% of a lubricant and 0.5-8% of a protectant.

[0070] More preferably, it includes 2-8% of (a) a hydrophilic colloid with a freezing power of 120 Brønsted or more, 3-6% of (b) a disintegrant, 80-90% of (c) a filler, 1-5% of a lubricant and 2-8% of a protectant.

[0071] For the disintegrating solid composition of the present invention, the hardness is preferably greater than 4N, more preferably greater than 7N, and even more preferably greater than 8N; and the disintegration time in water is 1 to 15 s, more preferably 1 to 10 s, and even more preferably 1 to 5 s.

[0072] Furthermore, in the disintegrating solid composition of the present invention, for example, to improve properties such as adhesiveness and tablet palatability, any other additives known to those skilled in the art, other than the aforementioned components, may be suitably added within a range that does not impair the effects of the present invention obtained from the above-described components. These additives include, but are not limited to, disintegrants, excipients, flow aids, sweeteners, flavoring agents, fragrances, and colorings.

[0073] A second aspect of the present invention provides the use of the above-described disintegrating solid composition in mixing the disintegrating solid composition with a pharmaceutically active ingredient in a stable and effective amount to form a pharmaceutical formulation.

[0074] The disintegrating solid composition of the present invention can be prepared simply using technically well-known methods and conventional equipment. For example, the components can be physically combined simply by dissolving, mixing, blending, stirring, or shaking until a homogeneous mixture is obtained. This mixture is then blended with the pharmaceutical active ingredient during processing. The disintegrating solid composition and the pharmaceutical active ingredient can be physically blended in any conventional manner until both are completely dispersed throughout the formulation, resulting in a pharmaceutical preparation containing the disintegrating solid composition and the pharmaceutical active ingredient of the present invention. In typical commercial practice, this can be accomplished by lyophilization. Preferably, the pharmaceutical active ingredient can be added separately to the premixed form of the disintegrating solid composition or to each dispersed component of the disintegrating solid composition.

[0075] A third aspect of the present invention provides an orally disintegrating solid dosage form comprising a bioactive ingredient (preferably a pharmacologically active ingredient) and the above-described disintegrating solid composition. Preferably, the pharmacologically active ingredient is added to the disintegrating solid composition in an amount of 50 w / w or less of the dosage form; more preferably, the pharmacologically active ingredient is added to the disintegrating solid composition in an amount of 20 w / w or less of the dosage form; and even more preferably, the pharmacologically active ingredient is added to the disintegrating solid composition in an amount of 2 to 20 w / w of the dosage form.

[0076] In the disintegrating solid compositions of the present invention, commonly used bioactive ingredients (preferably pharmacologically active ingredients) may be mixed in, without impairing the desired effects of the invention. The present invention does not limit the bioactive ingredients (preferably pharmacologically active ingredients) to any effective ingredient in the field of therapeutics or preventative medicine. These bioactive ingredients (preferably pharmacologically active ingredients) may be included in the compositions of the present invention or may be added separately to the formulation.

[0077] The bioactive ingredients include active compounds and compounds for veterinary and human use, such as including but not limited to pharmacodynamic ingredients (pharmaceutical active compounds), nutritional products, cosmeceuticals, cosmetics, natural products, vitamins, foods, nutritional supplements, biological agents, amino acids, proteins, nucleotides, and nucleic acids. In a preferred embodiment, the bioactive ingredients are suitable for oral administration.

[0078] Examples of such active ingredients include: hypnotics and sedatives, sleep inducers, anxiolytics, antiepileptics, antidepressants, anti-Parkinson's drugs, psychotropic drugs, central nervous system drugs, local anesthetics, skeletal muscle relaxants, vegetative-nervous system drugs, antipyretics, analgesics, anti-inflammatory drugs, antispasmodics, sedatives, cardiotonics, antiarrhythmics, diuretics, antihypertensives, vasoconstrictors, vasodilators, circulatory system drugs, drugs for hyperlipidemia, respiratory stimulants, antitussives, expectorants, antitussive and expectorant bronchodilators, antidiarrheals, intestinal regulators, peptic ulcer drugs, stomachic and digestive agents, antacids, laxatives, choleretics, digestive system drugs, adrenal hormones, hormone preparations, urinary system drugs, vitamin preparations, and hemostatic agents. This product range includes medications for liver diseases, gout, diabetes, antihistamines, antibiotics, antibacterial agents, antitumor agents, chemotherapy agents, cold remedies, tonics, and osteoporosis medications. Examples include indomethacin, diclofenac, diclofenac sodium, codeine, ibuprofen, phenylbutazone, hydroxyphenylbutazone, mepirizol, aspirin, ethylsalicylic acid, acetaminophen, aminopyrine, phenacetin, scopolamine bromide, morphine, itidolin, analgesics, fenprofen calcium, naproxen, celecoxib, valdecoxib, tramadol, and other anti-inflammatory, antipyretic, antispasmodic, or analgesic drugs; it also includes antirheumatic drugs such as itidotropic acid; antituberculosis drugs such as isoniazid and ethambutol hydrochloride; and nitrates. Isosorbide dinitrate, nitroglycerin, nifedipine, barnidipine hydrochloride, nicardipine hydrochloride, dipyridamole, amrinone, indanolol hydrochloride, hydralazine hydrochloride, methyldopa, furosemide, spironolactone, guanethidine nitrate, reserpine, amisulol hydrochloride, lisinopril, metronidazole, pilocarpine, paroxetine, and other circulatory system drugs; chlorpromazine hydrochloride, amitriptyline hydrochloride, nemopikelide, haloperidol, mopiperone hydrochloride, perphenazine, diazepam, lorazepam, nitrazepam, aldazol, alprazolam, methylphenidate, mirtazapine, risperidone, sodium valproate, and other antipsychotics; metoclopramide, ramosetron hydrochloride, granisetron hydrochloride, ondansetron hydrochloride, azasetron hydrochloride, and other antiemetics; chlorpheniramine maleate, diphenhydramine hydrochloride, and other antihistamines. Vitamins such as thiamine nitrate, vitamin E acetate, cyproheptadine, pyridoxal phosphate, adenosylcobalamin, ascorbic acid, and nicotinamide; gout medications such as allopurinol, colchicine, and probenecid; Parkinson's disease medications such as levodopa and selegiline; hypnotics and sedatives such as amobarbital, bromoisovora, midazolam, chloral hydrate, and dexmedetomidine; anti-tumor drugs such as fluorouracil, carmoflurane, arubicin hydrochloride, cyclophosphamide, and thiotepa; anti-allergy drugs such as pseudoephedrine and terfenadine; decongestants such as phenylpropanolamine and ephedrines; diabetes medications such as acesulfame potassium, insulin, tolbutamide, desmopressin, and glipizide; diuretics such as hydrochlorothiazide, porimethazine, and triamterene; and bronchodilators such as aminophylline, formoterol fumarate, and theophylline.Antitussives such as codeine phosphate, noscapine, dimethicone phosphate, and dextromethorphan; antiarrhythmic drugs such as quinidine nitrate, digitoxin, propafenone hydrochloride, and procainamide; topical anesthetics such as ethyl aminobenzoate, lidocaine, and cincocaine hydrochloride; antiepileptic drugs such as phenytoin, ethosuximide, and primidone; synthetic corticosteroids such as hydrocortisone, prednisolone, triamcinolone, and betamethasone; digestive system medications such as famotidine, ranitidine hydrochloride, cimetidine, sucralfate, sulpiride, teprenone, pranotoxin, 5-aminosalicylic acid, sulfasalazine, omeprazole, and lansoprazole; and drugs such as indanoxin, idebenone, sulpiride hydrochloride, and diphenylmetholone hydrochloride. Central nervous system medications such as phenobarbital and calcium pantothenate; hyperlipidemia treatment agents such as pravastatin sodium, simvastatin, lovastatin, fluvastatin, and atorvastatin; antibiotics such as phthalimilol hydrochloride, cefotetan, and josamycin; BPH treatment agents such as tamsulosin hydrochloride, doxazosin mesylate, and terazosin hydrochloride; anti-asthma agents such as pravastatin, zafirlukast, salbutamol, ambroxol, budesonide, and levosalbutamol; peripheral circulation improvers, antithrombotic agents, antihypertensive agents, heart failure treatment agents, treatment agents for various complications of diabetes, peptic ulcer treatment agents, skin ulcer treatment agents, hyperlipidemia treatment agents, and anti-asthma agents, including beraprost sodium. Medications can be used in their free form or any pharmaceutically permissible salt form.

[0079] Among the aforementioned pharmacologically active ingredients, central nervous system drugs are preferred in this invention. Examples of such pharmacologically active ingredients include, for instance, the antidepressants citalopram, ecitalopram oxalate, fluoxetine, fluvoxamine, paroxetine, and sertraline; venlafaxine and duloxetine; camel pine, isoproterenol, isocarboxamide, nicotinamide, phenelzine, selegiline, toloxacin, tranexamic acid, bromofaramine, moclobemide; amitriptyline, amoxapine, bupirocin, clomipramine, desipramine, diphenhydramine, duthiram, doxepin, imipramine, eplelide, lofepramine, and melitrix. Trimeprazole, nortriptyline, opilamol, protriptyline, trimeramine; maprotiline, mianserin, nefazodone, trazodone, their pharmaceutically acceptable salts, isomers and combinations thereof; mood stabilizers lithium carbonate, lithium orotate, lithium salts, valproic acid, sodium divalproate, sodium valproate, lamotrigine, carbamazepine, gabapentin, oxcarbazepine, topiramate, dexmedetomidine, their pharmaceutically acceptable salts, isomers and combinations thereof; herbal antidepressants St. John's wort; kavakava; echinacea; saw palmetto; holy basil; valerian; milk thistle; Siberian ginseng; Korean ginseng; ashwagandha root; nettle; ginkgo; centella asiatica; Ginkgo / Centella asiatica; Astragalus membranaceus; Goldenseal; Angelica sinensis; Ginseng; St. John's wort; Echinacea purpurea; Blueberry, Green tea; Hawthorn; Ginger, Ginkgo, Turmeric; Frankincense; Black cohosh; Cat's paw; Catnip; Chamomile; Dandelion; Chaenomeles speciosa; Black elderberry; White chrysanthemum; Garlic; Horse chestnut; Licorice extract; Red clover flowers and Rhodiola rosea leaves; Coleus forsythia; Passionflower; Eyebright; Yohimbine; Blueberry plants; Black pepper plants; Centella asiatica; Astragalus membranaceus; Valerian; Poppy root and grape seed; Verbena; Echinacea root; Plants of the genus *Cephalotaxus*; Sedatives and their combinations; Antipsychotic drugs Haloperidol, Chlorpromazine, Fluphenazine, Perphenazine, Prochlorperazine Thiopyridazine, trifluoperazine, metamethopyridazine, promethazine, trifluprozine, levoprozine, isoprozine, chlorprothiazine, sulfathiol, thiophene, clozapine, olanzapine, risperidone, buspirone, quetiapine, amisulpride, palpanidone, dopamine, bifenprox, norclozapine, aripiprazole, buphenazine, cannabidiol, fluperidone, loxapine, mesoridazine, indole, pimozide, prochlorperazine, thioridazine, tevothiazol, trifluoperazine, quetiapine, and ziprasidone, their pharmaceutically acceptable salts, isomers, and combinations thereof.

[0080] Furthermore, the aforementioned active ingredients can be used alone or in combination. Regarding the dosage of the active ingredient, there is generally no particular limitation as long as it is therapeutically effective; however, it is preferable to be below 50 w / w% relative to the tablet weight, more preferably below 20 w / w%, and even more preferably 2–20 w / w% or 0.2%–2.5%.

[0081] There are no specific limitations on the particle size of the aforementioned active ingredients, as long as there is no roughness in the oral cavity. For example, a good average particle size is generally 0.1–350 μm, even better is 5–250 μm, and ideally it is 50–250 μm. When the particle size is less than 0.1 μm, it is difficult for the active ingredient to act on the accurate location, affecting the efficacy of the drug; when it is greater than 350 μm, the discomfort in the oral cavity will increase.

[0082] Because the oral disintegrating solid dosage form described above contains the disintegrating particulate composition of the present invention, it has excellent properties such as hardness, disintegration, and formability. That is, as shown in the various embodiments of this specification, for example, the hardness of the oral disintegrating solid dosage form is greater than 4N, more preferably greater than 7N, and even more preferably greater than 8N; and the disintegration time in water is 1 to 15 seconds, more preferably 1 to 10 seconds, and even more preferably 1 to 5 seconds.

[0083] The present invention does not particularly limit the shape of the orally disintegrating solid dosage form; it can be any shape of tablet. More specifically, the orally disintegrating solid dosage form of the present invention can be an oral tablet, an effervescent tablet, a dispensing tablet, a chewable tablet, a tablet, an oral or sublingual tablet, an oral patch, an oral adhesive tablet, or an oral film. For the desired effect, any one of the following is more suitable: a sublingual tablet, a chewable tablet, a tablet, an oral patch, an oral adhesive tablet, or an oral film.

[0084] Furthermore, without compromising the intended effects of the present invention, the orally disintegrating solid dosage form may further comprise any ingredients known to those skilled in the art in order to adjust properties such as disintegration force, adhesiveness, and tablet feel. Examples of such ingredients include, for instance, gliding agents, inorganic excipients, sweeteners, flavorings, and colorings.

[0085] The fourth aspect of this invention provides a method for preparing the above-mentioned orally disintegrating solid dosage form. The solid dosage form can be any one of sublingual tablets, chewable tablets, tablets, oral patches, oral adhesive tablets, and oral films. The preparation steps include: adding a hydrophilic colloid to a solvent at 30-60°C, stirring until completely dissolved, cooling to room temperature, then adding a disintegrant, a filler, and a pharmaceutical ingredient, stirring until homogeneous, and then injecting a sample into an aluminum-plastic blister pack and processing it by heat treatment, solvent evaporation, or sublimation.

[0086] To obtain finished tablets of the same specifications, equal volumes of the mixed materials are typically taken and the solvent is removed under the same conditions through heat treatment or solvent evaporation. To further enhance drug activity and to better suit the active ingredient that forms a poorly water-soluble dimer in a solvent such as water, lyophilization is preferred to remove the solvent. The solvent can be water, ethanol, propylene glycol, tert-butanol, etc. Typically, the amount of solvent used is sufficient to maintain the total mass of the composition in the solvent at a mass percentage of 10% to 40%. Alternatively, when the active ingredient is relatively stable, tablets can be prepared using compression molding methods known in the art, including but not limited to direct compression and indirect compression.

[0087] Beneficial Effects: The disintegrating solid composition of the present invention uses gelatin with suitable lyophilization strength as a lyophilization scaffold, and L-HPC and CMC-Na or cross-linked CMC-Na as disintegrants. Due to their synergistic effect, it can impart excellent tablet hardness and disintegration properties required for various disintegrating tablets, and achieve excellent formability during tablet preparation. In particular, the disintegrating solid composition composed of gelatin, L-HPC, and CMC-Na with a lyophilization strength of 220 has a hardness greater than 4N, preferably greater than 7N, and more preferably greater than 8N; and a disintegration time in water of 1–15 s, more preferably 1–10 s, and more preferably 1–5 s; in addition, the composition has good formability, no breakage, no residue, is suitable for aluminum-plastic blister packs, has a good taste, and is non-irritating to the oral mucosa. Therefore, this disintegrating solid composition can serve as a formulation platform for blending various pharmacodynamic ingredients to ultimately achieve the purpose of treating different diseases. Detailed Implementation

[0088] The present invention will be specifically described below through embodiments. These embodiments are only for further explanation of the present invention and should not be construed as limiting the protection of the present invention. Non-essential corrections and adjustments made by those skilled in the art based on the above-described invention are still within the scope of protection of the present invention.

[0089] Unless otherwise specified, the raw materials (including active pharmaceutical ingredients and excipients) and equipment used in the embodiments or test examples are as follows:

[0090] 1) Raw materials:

[0091]

[0092]

[0093] 2) Auxiliary materials:

[0094] Gelatin 120LB8 (120 Freezing Power) 2782413 Rousselot (Guangdong) Gelatin Co., Ltd. Gelatin 220LB8 (220 Freezing Power) 2822835 Rousselot (Guangdong) Gelatin Co., Ltd. Gelatin 250LB 8 (250 Freezing Power) 2820768 Rousselot (Guangdong) Gelatin Co., Ltd. Starch (potato starch) VNL95 Guangzhou Hecheng Industrial Co., Ltd. CMC-Na 7LF (41 mPa·s, 0.7) NPE-0017 Shanghai Senjun Chemical Preparations & Excipients Co., Ltd. Crosslinked CMC-Na 71119070409 Shanghai Fenghong Pharmaceutical Excipients Technology Co., Ltd. L-HPC, SH-LH21 190913 Anhui Shanhe Pharmaceutical Excipients Co., Ltd. Lactose, Super Tab 14SD 104CWLN DFE pharma glycine V019090690 Merck, Germany PEG1000 20200402 Nanjing Well Pharmaceutical Co., Ltd. Mannitol, 50C E244J Rogate

[0095] 3) Instruments:

[0096] freeze dryer Advantage XL-70 Virtis SP Scientific Tablet hardness tester YD-2 Tianjin Guoming Medical Equipment Co., Ltd.

[0097] Detection method:

[0098] Hardness was measured using a tablet hardness tester.

[0099] The disintegration time was tested according to the disintegration time limit test method in General Chapter 0921 of the Chinese Pharmacopoeia 2020.

[0100] Appearance and packaging residues are observed with the naked eye.

[0101] Example 1

[0102] Example 1 provides a disintegrating solid composition A1, the composition of which is shown in Table 1a below.

[0103] Table 1a

[0104]

[0105]

[0106] Preparation process: Add gelatin to 50℃ water and stir until completely dissolved. Then add starch and stir until completely dissolved. Cool to room temperature, add other raw materials and stir until completely dissolved. Then use a pipette to drop into aluminum-plastic blister packs, adding 261μL to each. Place in a freeze dryer and freeze dry for 5 hours. Take out and test the relevant physical properties. The results are shown in Table 1b below.

[0107] The test results are shown in Table 1b.

[0108] Table 1b

[0109] 38.5mg 4.2N 2s Smooth and flat No foreign body sensation No residue

[0110] Example 2

[0111] Example 2 provides a disintegrating solid composition A2, the composition of which is shown in Table 2a below.

[0112] Table 2a

[0113] starch 3 Gelatin (220 gel strength) 1 Mannitol 10.5 lactose 2 PEG1000 0.5 water 100

[0114] Preparation process: Gelatin was added to 50℃ water and stirred until completely dissolved. Then starch was added and stirred until completely dissolved. After cooling to room temperature, other raw materials were added and stirred until completely dissolved. 261μL was then added dropwise into aluminum-plastic blister packs using a pipette. The blister packs were freeze-dried for 5 hours and then removed. The relevant physical properties were tested, and the results are shown in Table 2b below.

[0115] Table 2b

[0116] 37mg 6.3N 1.5s Smooth and flat No foreign body sensation No residue

[0117] Example 3

[0118] Example 3 provides a disintegrating solid composition A3, the composition of which is shown in Table 3a below.

[0119] Table 3a

[0120] Gelatin (220 gel strength) 0.5 Mannitol 13.915 Crosslinked CMC-Na 0.085 lactose 2 PEG1000 0.5 water 100

[0121] Preparation process: Add gelatin to 50℃ water and stir until completely dissolved. Cool to room temperature, add other raw materials and stir until completely dissolved. Then, use a pipette to drop 261μL into each aluminum-plastic blister pack. Place the blister pack in a freeze dryer and freeze-dry for 5 hours. Take it out and test the relevant physical properties. The results are shown in Table 3b below.

[0122] Table 3b

[0123] 40mg 3.5N 1s Smooth and flat No foreign body sensation No residue

[0124] Example 4

[0125] Example 4 provides a disintegrating solid composition A4, the composition of which is shown in Table 4a below.

[0126] Table 4a

[0127] Gelatin (120 gel strength) 1 Mannitol 6.2075 Crosslinked CMC-Na 0.0425 lactose 1 PEG1000 0.25 water 50

[0128] Preparation process: Add gelatin to 50℃ water and stir until completely dissolved. Cool to room temperature, add other raw materials and stir until completely dissolved. Then, use a pipette to drop 261μL into each aluminum-plastic blister pack. Place the blister pack in a freeze dryer and freeze-dry for 5 hours. Take it out and test the relevant physical properties. The results are shown in Table 4 below.

[0129] Table 4b

[0130]

[0131]

[0132] Example 5

[0133] Example 5 provides a disintegrating solid composition A5, the composition of which is shown in Table 5a below.

[0134] Table 5a

[0135] Gelatin (250g gel strength) 0.5 Mannitol 6.2075 Crosslinked CMC-Na 0.0425 lactose 1 PEG1000 0.25 water 50

[0136] Preparation process: Add gelatin to 50℃ water and stir until completely dissolved. Cool to room temperature, add other raw materials and stir until completely dissolved. Then, use a pipette to drop 261μL into each aluminum-plastic blister pack. Place the blister pack in a freeze dryer and freeze-dry for 5 hours. Take it out and test the relevant physical properties. The results are shown in Table 5b below.

[0137] Table 5b

[0138] 40mg 8N 15s Smooth and flat slight foreign body sensation No residue

[0139] Example 6

[0140] Example 6 provides a disintegrating solid composition A6, the composition of which is shown in Table 6a below.

[0141] Table 6a

[0142] Gelatin (220 gel strength) 1 Mannitol 12.65 L-HPC 0.85 lactose 2 PEG1000 0.5 water 100

[0143] Preparation process: Add gelatin to 50℃ water and stir until completely dissolved. Cool to room temperature, add other raw materials and stir until completely dissolved. Then, use a pipette to drop 261μL into each aluminum-plastic blister pack. Place the blister pack in a freeze dryer and freeze-dry for 5 hours. Take it out and test the relevant physical properties. The results are shown in Table 6b below.

[0144] Table 6b

[0145] 38mg 8.2N 2s Smooth and flat Feeling of a foreign object No residue

[0146] Example 7

[0147] Example 7 provides a disintegrating solid composition A7, the composition of which is shown in Table 7a below.

[0148] Table 7a

[0149] Gelatin (220 gel strength) 0.5 Mannitol 5.825 L-HPC 0.425 lactose 1 glycine 0.5 PEG1000 0.25 water 50

[0150] Preparation process: Add gelatin to 50℃ water and stir until completely dissolved. Cool to room temperature, add other raw materials and stir until completely dissolved. Then, use a pipette to drop 261μL into each aluminum-plastic blister pack. Place the blister pack in a freeze dryer and freeze-dry for 5 hours. Take it out and test the relevant physical properties. The results are shown in Table 7b below.

[0151] Table 7b

[0152] 40mg 8.5N 3s Smooth and flat slight foreign body sensation No residue

[0153] Example 8

[0154] Example 8 provides a disintegrating solid composition A8, the composition of which is shown in Table 8a below.

[0155] Table 8a

[0156]

[0157]

[0158] Preparation process: Add gelatin to 50℃ water and stir until completely dissolved. Cool to room temperature, add other raw materials and stir until completely dissolved. Then, use a pipette to drop 261μL into each aluminum-plastic blister pack. Place the blister pack in a freeze dryer and freeze-dry for 5 hours. Take it out and test the relevant physical properties. The results are shown in Table 8b below.

[0159] Table 8b

[0160] 40mg 8.5N 2s Smooth and flat No foreign body sensation No residue

[0161] Example 9

[0162] Example 9 provides a disintegrating solid composition A9, the composition of which is shown in Table 9a below.

[0163] Table 9a

[0164] Gelatin (220 gel strength) 0.5 Mannitol 6.2875 CMC-Na 0.3083 L-HPC 0.1542 lactose 1 glycine 0.25 PEG1000 0.25 water 50

[0165] Preparation process: Add gelatin to 50℃ water and stir until completely dissolved. Cool to room temperature, add other raw materials and stir until completely dissolved. Then, use a pipette to drop 261μL into each aluminum-plastic blister pack. Place the blister pack in a freeze dryer and freeze-dry for 5 hours. Take it out and test the relevant physical properties. The results are shown in Table 9b below.

[0166] Table 9b

[0167] 40mg 9.3N 3s Smooth and flat No foreign body sensation No residue

[0168] Example 10

[0169] Example 10 provides a disintegrating solid composition A10, the composition of which is shown in Table 10a below.

[0170] Table 10a

[0171] Gelatin (220 gel strength) 0.5 Mannitol 6.2875 CMC-Na 0.3469 L-HPC 0.1156 lactose 1 glycine 0.25 PEG1000 0.25 water 50

[0172] Preparation process: Add gelatin to 50℃ water and stir until completely dissolved. Cool to room temperature, add other raw materials and stir until completely dissolved. Then, use a pipette to drop 261μL into each aluminum-plastic blister pack. Place the blister pack in a freeze dryer and freeze-dry for 5 hours. Take it out and test the relevant physical properties. The results are shown in Table 10b below.

[0173] Table 10b

[0174] 40mg 9.1N 3s Smooth and flat No foreign body sensation No residue

[0175] Example 11

[0176] Example 11 provides a disintegrating solid composition A11, the composition of which is shown in Table 11a below.

[0177] Table 11a

[0178]

[0179]

[0180] Preparation process: Add gelatin to 50℃ water and stir until completely dissolved. Cool to room temperature, add other raw materials and stir until completely dissolved. Then, use a pipette to drop 261μL into each aluminum-plastic blister pack. Place the blister pack in a freeze dryer and freeze-dry for 5 hours. Take it out and test the relevant physical properties. The results are shown in Table 11b below.

[0181] Table 11b

[0182] 40mg 10N 3s Smooth and flat No foreign body sensation No residue

[0183] Example 12

[0184] Example 12 provides an orally disintegrating sublingual tablet formulation C1, the composition of which is shown in Table 12a below.

[0185] Table 12a

[0186] Dexmedetomidine hydrochloride 0.017535 Gelatin (220 gel strength) 0.5 Mannitol 6.2875 CMC-Na 0.25 L-HPC 0.2125 lactose 1 glycine 0.25 PEG1000 0.25 water 50

[0187] Preparation process: Add gelatin to 50℃ water and stir until completely dissolved. Cool to room temperature, add other raw materials and stir until completely dissolved. Then, use a pipette to drop 261μL into each aluminum-plastic blister pack. Place the blister pack in a freeze dryer and freeze-dry for 5 hours. Take it out and test the relevant physical properties. The results are shown in Table 12b below.

[0188] Table 12b

[0189] 40mg 9N 3s Smooth and flat / No residue

[0190] Example 13

[0191] Example 13 provides an orally disintegrating sublingual tablet formulation C2, the composition of which is shown in Table 13a below.

[0192] Table 13a

[0193] Butspirone 0.2245 Gelatin (220 gel strength) 0.5 Mannitol 6.2875 CMC-Na 0.25 L-HPC 0.2125 lactose 1 glycine 0.25 PEG1000 0.25 water 50

[0194] Preparation process: Add gelatin to 50℃ water and stir until completely dissolved. Cool to room temperature, add other raw materials and stir until completely dissolved. Then, use a pipette to drop 261μL into each aluminum-plastic blister pack. Place the blister pack in a freeze dryer and freeze-dry for 5 hours. Take it out and test the relevant physical properties. The results are shown in Table 13b below.

[0195] Table 13b

[0196] 40mg 11N 1s Smooth and flat No foreign body sensation No residue

[0197] Example 14

[0198] Example 14 provides an orally disintegrating sublingual tablet formulation C3, the composition of which is shown in Table 14a below.

[0199] Table 14a

[0200]

[0201]

[0202] Preparation process: Add gelatin to 50℃ water and stir until completely dissolved. Cool to room temperature, add other raw materials and stir until completely dissolved. Then, use a pipette to drop 261μL into each aluminum-plastic blister pack. Place the blister pack in a freeze dryer and freeze-dry for 5 hours. Take it out and test the relevant physical properties. The results are shown in Table 14b below.

[0203] Table 14b

[0204] 40mg 10N 3s Smooth and flat No foreign body sensation No residue

[0205] Example 15

[0206] Example 15 provides an orally disintegrating sublingual tablet formulation C4, the composition of which is shown in Table 15a below.

[0207] Table 15a

[0208] Risperidone 0.2245 Gelatin (220 gel strength) 0.5 Mannitol 6.2875 CMC-Na 0.25 L-HPC 0.2125 lactose 1 glycine 0.25 PEG1000 0.25 water 50

[0209] Preparation process: Add gelatin to 50℃ water and stir until completely dissolved. Cool to room temperature, add other raw materials and stir until completely dissolved. Then, use a pipette to drop 261μL into each aluminum-plastic blister pack. Place the blister pack in a freeze dryer and freeze-dry for 5 hours. Take it out and test the relevant physical properties. The results are shown in Table 15b below.

[0210] Table 15b

[0211] 40mg 11N 2s Smooth and flat No foreign body sensation No residue

[0212] Comparative Example 1

[0213] Comparative Example 1 provides a disintegrating solid composition B1, the composition of which is shown in Table 1c below.

[0214] Table 1c

[0215] Gelatin (220 gel strength) 0.5 Mannitol 6.2875 Crosslinked CMC-Na 0.1542 L-HPC 0.3083 lactose 1 glycine 0.25 PEG1000 0.25 water 50

[0216] Preparation process: Add gelatin to 50℃ water and stir until completely dissolved. Cool to room temperature, add other raw materials and stir until completely dissolved. Then, use a pipette to drop 261μL into each aluminum-plastic blister pack. Place the blister pack in a freeze dryer and freeze-dry for 5 hours. Take it out and test the relevant physical properties. The results are shown in Table 1d below.

[0217] Table 1d

[0218] 40mg 6.2N 3s Smooth and flat No foreign body sensation Small amount of residue

[0219] Comparative Example 2

[0220] Comparative Example 2 provides a disintegrating solid composition B2, the composition of which is shown in Table 2c below.

[0221] Table 2c

[0222] Gelatin (220 gel strength) 0.5 Mannitol 6.2875 Crosslinked CMC-Na 0.3083 L-HPC 0.1542 lactose 1 glycine 0.25 PEG1000 0.25 water 50

[0223] Preparation process: Add gelatin to 50℃ water and stir until completely dissolved. Cool to room temperature, add other raw materials and stir until completely dissolved. Then, use a pipette to drop 261μL into each aluminum-plastic blister pack. Place the blister pack in a freeze dryer and freeze-dry for 5 hours. Take it out and test the relevant physical properties. The results are shown in Table 2d below.

[0224] Table 2d

[0225] 40mg 5.3N 3s Smooth and flat No foreign body sensation Small amount of residue

[0226] Comparative Example 3

[0227] Comparative Example 3 provides a disintegrating solid composition B3, the composition of which is shown in Table 3c below.

[0228] Table 3c

[0229] Gelatin (220 gel strength) 0.5 Mannitol 6.2875 Crosslinked CMC-Na 0.1156 L-HPC 0.3469 lactose 1 glycine 0.25 PEG1000 0.25 water 50

[0230] Preparation process: Add gelatin to 50℃ water and stir until completely dissolved. Cool to room temperature, add other raw materials and stir until completely dissolved. Then, use a pipette to drop 261μL into each aluminum-plastic blister pack. Place the blister pack in a freeze dryer and freeze-dry for 5 hours. Take it out and test the relevant physical properties. The results are shown in Table 3d below.

[0231] Table 3d

[0232] 40mg 2.2N 4s Smooth and flat No foreign body sensation serious residues

[0233] Comparative Example 4

[0234] Comparative Example 4 provides a disintegrating solid composition B4, the composition of which is shown in Table 4c below.

[0235] Table 4c

[0236] Gelatin (220 gel strength) 0.5 Mannitol 6.2875 Crosslinked CMC-Na 0.3469 L-HPC 0.1156 lactose 1 glycine 0.25 PEG1000 0.25 water 50

[0237] Preparation process: Add gelatin to 50℃ water and stir until completely dissolved. Cool to room temperature, add other raw materials and stir until completely dissolved. Then, use a pipette to drop 261μL into each aluminum-plastic blister pack. Place the blister pack in a freeze dryer and freeze-dry for 5 hours. Take it out and test the relevant physical properties. The results are shown in Table 4d below.

[0238] Table 4d

[0239] 40mg 1.2N 5s Smooth and flat No foreign body sensation serious residues

[0240] Comparative Example 5

[0241] Comparative Example 5 provides a disintegrating solid composition B5, the composition of which is shown in Table 5c below.

[0242] Table 5c

[0243]

[0244]

[0245] Preparation process: Add gelatin to 50℃ water and stir until completely dissolved. Cool to room temperature, add other raw materials and stir until completely dissolved. Then, use a pipette to drop 261μL into each aluminum-plastic blister pack. Place the blister pack in a freeze dryer and freeze-dry for 5 hours. Take it out and test the relevant physical properties. The results are shown in Table 5d below.

[0246] Table 5d

[0247] 40mg 10.0N 2s Smooth and flat No foreign body sensation serious residues

[0248] Comparative Example 6

[0249] Comparative Example 6 provides a disintegrating solid composition B6, the composition of which is shown in Table 6c below.

[0250] Table 6c

[0251] Gelatin (220 gel strength) 0.5 Mannitol 5.9575 CMC-Na 0.5 Crosslinked CMC-Na 0.0425 lactose 1 glycine 0.25 PEG1000 0.25 water 50

[0252] Preparation process: Add gelatin to 50℃ water and stir until completely dissolved. Cool to room temperature, add other raw materials and stir until completely dissolved. Then, use a pipette to drop 261μL into each aluminum-plastic blister pack. Place the blister pack in a freeze dryer and freeze-dry for 5 hours. Take it out and test the relevant physical properties. The results are shown in Table 6d below.

[0253] Table 6d

[0254] 40mg 10.2N 22s Smooth and flat No foreign body sensation serious residues

[0255] Comparative Example 7

[0256] Comparative Example 7 provides a disintegrating solid composition B7, the composition of which is shown in Table 7c below.

[0257] Table 7c

[0258] Gelatin (220 gel strength) 0.5 Mannitol 6.2875 CMC-Na 0.1542 L-HPC 0.3083 lactose 1 glycine 0.25 PEG1000 0.25 water 50

[0259] Preparation process: Add gelatin to 50℃ water and stir until completely dissolved. Cool to room temperature, add other raw materials and stir until completely dissolved. Then, use a pipette to drop 261μL into each aluminum-plastic blister pack. Place the blister pack in a freeze dryer and freeze-dry for 5 hours. Take it out and test the relevant physical properties. The results are shown in Table 7d below.

[0260] Table 7d

[0261] 40mg 13.4N 2s Smooth and flat No foreign body sensation Small amount of residue

[0262] Comparative Example 8

[0263] Comparative Example 8 provides a disintegrating solid composition B8, the composition of which is shown in Table 8c below.

[0264] Table 8c

[0265]

[0266]

[0267] Preparation process: Add gelatin to 50℃ water and stir until completely dissolved. Cool to room temperature, add other raw materials and stir until completely dissolved. Then, use a pipette to drop 261μL into each aluminum-plastic blister pack. Place the blister pack in a freeze dryer and freeze-dry for 5 hours. Take it out and test the relevant physical properties. The results are shown in Table 8 below.

[0268] Table 8d

[0269] 40mg 6.8N 5s Smooth and flat No foreign body sensation Small amount of residue

[0270] Comparative Example 9

[0271] Comparative Example 9 provides a disintegrating solid composition B9, the composition of which is shown in Table 9c below.

[0272] Table 9c

[0273] Gelatin (220 gel strength) 0.5 Mannitol 6.2875 CMC-Na (7HF pH; 1914 mPa·s) 0.25 L-HPC 0.2125 lactose 1 glycine 0.25 PEG1000 0.25 water 50

[0274] Preparation process: Add gelatin to 50℃ water and stir until completely dissolved. Cool to room temperature, add other raw materials and stir until completely dissolved. Then, use a pipette to drop 261μL into each aluminum-plastic blister pack. Place the blister pack in a freeze dryer and freeze-dry for 5 hours. Take it out and test the relevant physical properties. The results are shown in Table 9d below.

[0275] Table 9d

[0276] 40mg 5N 5s Smooth and flat No foreign body sensation No residue

[0277] The above description is merely an embodiment of the present invention and is not intended to limit the invention in any other way. Any person skilled in the art may make changes or equivalent variations based on the above-disclosed technical content. Any simple modifications, equivalent variations, and alterations made to the above embodiments based on the technical essence of the present invention without departing from the technical solution of the present invention shall still fall within the protection scope of the technical solution of the present invention.

Claims

1. A disintegrating solid composition, characterized in that, It contains gelatin and a disintegrant, wherein the gelatin content is 3% to 12% of the total mass of the solid composition; The disintegrant is low-substituted hydroxypropyl cellulose or a combination of (b1) sodium carboxymethyl cellulose and (b2) low-substituted hydroxypropyl cellulose, and the mass ratio of (b1):(b2) is (1~3):1, the mass ratio of gelatin to disintegrant is (1~2):1, and the gelatin gel strength is 220~250 brunc; or, The disintegrant is croscarmellose sodium, the mass ratio of gelatin to croscarmellose sodium is (20~25):1, and the gelatin gel strength is 120 brunc; or... The disintegrant is croscarmellose sodium, the mass ratio of gelatin to croscarmellose sodium is (12~13):1, and the gelatin gel strength is 220~250 brunc.

2. The disintegrating solid composition according to claim 1, characterized in that, The disintegrant is low-substituted hydroxypropyl cellulose or a combination of (b1) sodium carboxymethyl cellulose and (b2) low-substituted hydroxypropyl cellulose. The mass ratio of gelatin to disintegrant is (1~2):1, and the gelatin content accounts for 5%~7% of the total mass of the solid composition.

3. The disintegrating solid composition according to claim 1, characterized in that, The disintegrant is croscarmellose sodium, the gelatin gel strength is 120 Brønsted, the mass ratio of gelatin to croscarmellose sodium is (23~24):1, and the gelatin content accounts for 10%~12% of the total mass of the solid composition; Alternatively, the disintegrant is croscarmellose sodium, the gelatin gel strength is 220-250 brunc, the mass ratio of gelatin to croscarmellose sodium is (12-13):1, and the gelatin content accounts for 5%-7% of the total mass of the solid composition.

4. The disintegrating solid composition according to claim 1, characterized in that, The disintegrant is a combination of (b1) sodium carboxymethyl cellulose and (b2) low-substituted hydroxypropyl cellulose, and the mass ratio of (b1):(b2) is (1~3):1, the mass ratio of gelatin to disintegrant is (1~2):1; the gelatin content accounts for 5%~7% of the total mass of the solid composition.

5. The disintegrating solid composition according to any one of claims 1 to 4, characterized in that, It also includes at least one of fillers, lubricants, and protectants.

6. The disintegrating solid composition according to claim 5, characterized in that, The filler accounts for 70-98% of the total mass of the solid composition; The lubricant accounts for 0.0001% to 5% of the total mass of the solid composition; The protective agent accounts for 0.001% to 8% of the total mass of the solid composition.

7. The disintegrating solid composition according to claim 5, characterized in that, The filler accounts for 80-95% of the total mass of the solid composition.

8. The disintegrating solid composition according to claim 5, characterized in that, The lubricant accounts for 0.1-5% of the total mass of the solid composition.

9. The disintegrating solid composition according to claim 5, characterized in that, The protective agent accounts for 0.5 to 8% of the total mass of the solid composition.

10. The disintegrating solid composition according to claim 5, characterized in that, The filler comprises at least one of mannitol, erythritol, xylitol, trehalose, lactose, maltose, maltitol, glucose, sucrose, fructose, and sorbitol; The lubricant contains at least one of magnesium stearate, silica, talc, polyethylene glycol, and stearic acid; The protective agent comprises at least one of the following amino acids or salts: glycine, alanine, valine, leucine, isoleucine, serine, threonine, aspartic acid, glutamic acid, asparagine, glutamine, lysine, arginine, cysteine, methionine, phenylalanine, histidine, tryptophan, or proline.

11. The disintegrating solid composition according to claim 10, characterized in that, The lubricant contains polyethylene glycol 1000 or polyethylene glycol 2000.

12. The disintegrating solid composition according to claim 10 or 11, characterized in that, The protective agent contains glycine, lysine, arginine, or histidine.

13. The disintegrating solid composition according to claim 5, characterized in that, The filler is one or more of mannitol, erythritol, xylitol, trehalose, or lactose.

14. The disintegrating solid composition according to claim 5, characterized in that, The filler is mannitol and lactose, wherein the mass ratio of lactose to mannitol is 1:(4~10).

15. The disintegrating solid composition according to claim 14, characterized in that, The mass ratio of lactose to mannitol is 1:(4~8).

16. The disintegrating solid composition according to claim 14, characterized in that, The mass ratio of lactose to mannitol is 1:(5.5~6.5).

17. An orally disintegrating solid dosage form, characterized in that, The solid formulation includes a bioactive ingredient and a disintegrating solid composition according to any one of claims 1 to 16, wherein the content of the bioactive ingredient is less than 20% of the weight of the solid formulation.

18. The orally disintegrating solid dosage form according to claim 17, characterized in that, The content of the bioactive ingredient is 2-20% of the weight of the solid dosage form.

19. The orally disintegrating solid dosage form according to claim 17, characterized in that, The content of the bioactive ingredient is 0.2% to 2.5% of the weight of the solid dosage form.

20. The orally disintegrating solid dosage form according to claim 17, characterized in that, The bioactive ingredient is a central nervous system drug.

21. The orally disintegrating solid dosage form according to claim 17, characterized in that, The bioactive ingredients are selected from dexmedetomidine, citalopram, escitalopram oxalate, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine, duloxetine, phenelzine, selegiline, toloxacin, transphenylcyclopropionamide, bromofaromin, moclobemide, amitriptyline, amoxapine, clomipramine, desipramine, duthiram, doxepin, imipramine, melitraline, nortriptyline, protriptyline, maprotiline, mianserin, nefazodone, trazodone, lithium orotate, sodium valproate, sodium valproate. Lamotrigine, carbamazepine, gabapentin, oxcarbazepine, topiramate, haloperidol, chlorpromazine, fluphenazine, perphenazine, trifluoperazine, promethazine, trifluprozine, promethazine, sulfamethoxazole, cyclophosphamide, clozapine, olanzapine, risperidone, buspirone, quetiapine, amisulpride, paliperidone, dopamine, aripiprazole, buphenazine, cannabidiol, fluperidone, loxapine, mesoridazine, indole, pimozide, prochlorperazine, thioridazine, tevothixoxanone, trifluoperazine, quetiapine, or ziprasidone.

22. The orally disintegrating solid dosage form according to any one of claims 18-21, characterized in that, The solid dosage form is any one of sublingual tablets, chewable tablets, lozenges, oral patches, oral adhesive tablets, and oral films.

23. A method for preparing a disintegrating solid composition according to any one of claims 1 to 16, or a method for preparing an orally disintegrating solid dosage form according to any one of claims 17 to 21, characterized in that, include: Add gelatin to a solvent at 30-60℃ and stir until completely dissolved. Cool to room temperature, add a disintegrant, and optionally add fillers, lubricants, protectants, and bioactive ingredients. Stir until homogeneous, take a sample and inject it into an aluminum-plastic blister pack. Process the sample by heat treatment, solvent evaporation, or sublimation.

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