CN110742868A - Mirogabalin Besilate orally disintegrating tablet - Google Patents

Mirogabalin Besilate orally disintegrating tablet Download PDF

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CN110742868A
CN110742868A CN201911141620.6A CN201911141620A CN110742868A CN 110742868 A CN110742868 A CN 110742868A CN 201911141620 A CN201911141620 A CN 201911141620A CN 110742868 A CN110742868 A CN 110742868A
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besilate
orally disintegrating
disintegrating tablet
mannitol
miroalbalin
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戴德标
陆文通
裴九宏
吴丽萍
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HEFEI TOPWAY BIOTECHNOLOGY CO Ltd
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HEFEI TOPWAY BIOTECHNOLOGY CO Ltd
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    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

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Abstract

The invention discloses a miroabalalin Besilate orally disintegrating tablet, which comprises the following raw materials in percentage by weight: 5-6.5% of Mirogabalin Besilate, 70-87% of filler, 2.5-15% of disintegrant, 0-2.18% of lubricant, 0-10% of macromolecular coating agent, 0-5% of colorant, 0-10% of adhesive, 0.5-2% of flavoring agent and 0.2-2% of spice, wherein the total weight percentage of the raw materials is 100%, and the filler is at least one of D-mannitol, crystalline cellulose, corn starch, trehalose and hydroxypropyl methylcellulose. The present invention has the same tablet hardness and appropriate mechanical strength as those of ordinary tablets, and can shorten the disintegration time in the oral cavity.

Description

Mirogabalin Besilate orally disintegrating tablet
Technical Field
The invention relates to the technical field of medicines, and in particular relates to a Mirogabalin Besilate orally disintegrating tablet.
Background
In general, the initial dose of an adult patient is 5mg, taken orally 2 times daily, and then gradually increased by 5mg at intervals of at least one week until 15mg, the dose can be suitably adjusted between 10mg and 15mg according to age and symptoms, and taken orally 2 times daily, and Mirogabalin (DS-5565) is a ligand of α 2 delta-1, and when they are combined, the inflow of calcium ions at nerve endings can be reduced, thereby reducing the release of pain-related neurotransmitters.
Miroabalin Besilate; its chemical name is [ (1R, 5S, 6S) -6- (aminomethyl) -3 ethylbicyclo [3.2.0 ]]Hept-3-en-6-yl]Acetic acid monomethanesulfonate salt; CAS number 1138245-21-2; the molecular formula is C12H19NO2·C6H6O3S; the molecular weight is 367.46; it is a white to yellowish powder; no smell, bitter taste; the melting point is 169 ℃; dissolving in 1, 3-dimethyl-2-imidazolidinone, methanol and absolute ethyl alcohol, slightly dissolving in water, being insoluble in acetone, being almost insoluble in acetonitrile, and being very insoluble in anisole and methyl tert-butyl ether; the dissociation constants are: pKa of the pKa1: 4.1 (carboxyl group), pKa2: 11.0 (amino); the distribution coefficient is: log P: -0.59(ph 3.0); log P: -0.05(ph 7.5); log P: -1.10(ph 12.0); it is non-hygroscopic and is useful for the treatment of peripheral neuropathic pain; the structural formula is as follows:
Figure BDA0002281101440000021
the orally disintegrating tablet is a novel solid quick release preparation researched and developed at home and abroad in recent years, is convenient to take, can be quickly disintegrated into fine particles within 15-60s in the oral cavity without water or with only a small amount of water when being taken, can be taken by swallowing, has the advantages of quick absorption, quick response, small liver first pass effect, high bioavailability and the like, and is suitable for being taken by old people, children and patients with difficulty in swallowing or inconvenience in taking water.
Since the 80's of the last century, more than 80 orally disintegrating tablets have been marketed globally, with a sales of 10 billion dollars. In China, the albuterol orally disintegrating tablet (Kangershuning) developed by Chongqing Kangzhuer pharmaceutical Co., Ltd is produced in the national food and drug administration production batch at the 7-month rate in 2004, and the history of localization of the orally disintegrating tablet technology is opened. At present, the varieties on the market are increasingly increased at home, and 14 new drug production batches of orally disintegrating tablets are approved by 2007.
Tablets have long been the most commonly used dosage form. It has the advantages of convenient administration and carrying, stable quality, accurate dosage, high mechanization degree, low production cost, etc., thereby having wide application. However, the tablet has the defects of slow disintegration in vivo, low bioavailability and poor patient compliance, and is limited in application due to the difficulty in swallowing part of patients. It is estimated that 50% of patients do not respond to the prescribed formulation each year, and 30% feel difficulty in swallowing tablets and capsules or have difficulty swallowing, particularly in the elderly and children. Patient inadaptation to pharmaceutical formulations has been investigated resulting in annual U.S. losses of $ 1000 billion, affecting 10% of hospitalized patients.
The orally disintegrating tablet has the clinical significance of ① improving the compliance of patients, particularly patients with dysphagia, such as the old, children and other special crowds, ② used in emergency or environments with inconvenient water intake, ③ reducing the burden of medical institutions or families, ④ rapidly disintegrating in the oral cavity and having partial absorption, reducing the first pass effect of the liver and improving the bioavailability, ⑤ increasing new dosage forms of the medicine, prolonging the protection period of the medicine and improving the economic benefit.
The preparation technology of orally disintegrating tablets is mature abroad, such as a freeze drying method, a molding method, a direct tabletting method, a spray drying method and the like, although some varieties are successfully marketed in China, the products are still not as good as foreign in the aspects of taste and disintegration speed due to the limitation of intellectual property of the preparation technology. At present, the orally disintegrating tablets sold in the market abroad are all produced by a patent holder in a entrusted processing mode, and form a strict technical barrier. However, the preparation technology of orally disintegrating tablets which are marketed abroad has certain defects and is only suitable for certain specific small-dose medicines. At present, the development trend of the preparation technology of the orally disintegrating tablet is a uniform trend for further reducing the production cost and preparing the large-dose orally disintegrating tablet besides maintaining good disintegration, taste and mechanical strength.
The prior patent documents are: patent document 1: WO2009041453, bicyclic γ -amino acid derivatives; patent document 2: WO2014163132, solid compositions comprising aminocarboxylates; patent document 3: WO2016148263, solid formulation comprising an antioxidant; patent document 4: WO2016148264, a solid formulation comprising a colorant; patent document 5: WO2013089188, a process for optical resolution of bicyclic compounds using asymmetric catalysts; patent document 6: WO2015005298, a process for the preparation of optically active bicyclic γ -amino acid derivatives.
So far, no development report of an orally disintegrating tablet containing Mirogabalin Besilate exists. In view of the above, it would be desirable to provide new dosage forms that provide better relief from diabetic neuropathic pain, and which are inexpensive products that are safe and convenient to use and that last significantly longer. In particular, it would be highly desirable to develop a method for treating peripheral neuropathic pain that is fast to absorb, has high bioavailability, does not require administration with water, greatly improves compliance of children, the elderly, bedridden, and severely disabled patients, and avoids the first pass effect of the liver to more effectively treat peripheral neuropathic pain.
Disclosure of Invention
Based on the technical problems in the background art, the invention provides a Mirogabalin Besilate orally disintegrating tablet which has the same tablet hardness and moderate mechanical strength as the common tablet and can shorten the disintegration time in the oral cavity.
The invention provides a Mirogabalin Besilate orally disintegrating tablet which comprises the following raw materials in percentage by weight: 5-6.5% of Mirogabalin Besilate, 70-87% of filler, 2.5-15% of disintegrant, 0-2.18% of lubricant, 0-10% of macromolecular coating agent, 0-5% of colorant, 0-10% of adhesive, 0.5-2% of flavoring agent and 0.2-2% of spice, wherein the total weight percentage of the raw materials is 100%, and the filler is at least one of D-mannitol, crystalline cellulose, corn starch, trehalose and hydroxypropyl methylcellulose.
Preferably, the D-mannitol is a mixture of D-mannitol powder and D-mannitol particles, wherein the weight ratio of the D-mannitol powder to the D-mannitol particles is 1: 0.8-1.2.
Preferably, the particle size of the D-mannitol particles is 150-250 μm, and the D-mannitol powder is 150-250 mesh.
Preferably, 8-12 wt% of D-mannitol aqueous solution is taken for spray granulation to obtain the D-mannitol particles.
Preferably, the hypromellose is a mixture of hypromellose powder and hypromellose particles, wherein the weight ratio of the hypromellose powder to the hypromellose particles is 1: 0.8-1.2.
Preferably, the particle size of the hydroxypropyl methylcellulose particles is 150-250 mu m, and the particle size of the hydroxypropyl methylcellulose powder is 150-250 meshes.
Preferably, 8-12 wt% of hydroxypropyl methylcellulose water solution is adopted for spray granulation to obtain the hydroxypropyl methylcellulose particles.
Preferably, the disintegrant is at least one of hydroxypropyl cellulose, crospovidone, croscarmellose sodium.
Preferably, the lubricant is at least one of sodium stearyl fumarate, magnesium stearate and silicon dioxide.
Preferably, the high molecular coating agent is at least one of hydroxypropyl methylcellulose acetate succinate and powdery reduced maltose starch.
Preferably, the colorant is at least one of titanium dioxide and iron oxide.
Preferably, the binder is polyethylene glycol 400 or polyvinyl alcohol.
Preferably, the flavoring agent is at least one of acesulfame potassium, sucralose, aspartame, and saccharin sodium hydrate.
Preferably, the flavor is at least one of L-menthol and peppermint oil.
Preferably, the hardness of the miroalbalin Besilate orally disintegrating tablet is not less than 30N.
The specification, diameter, thickness and weight of the miroavailin Besilate orally disintegrating tablet are shown in the following table:
specification of 2.5 mg/tablet 5 mg/tablet 10 mg/tablet 15 mg/tablet
Diameter of 5.6-6.0mm 7.0-7.2mm 9.0-9.5mm 10.6-11.0mm
Thickness of 1.0-1.2mm 2.6-3.4mm 4.0-4.2mm 7.0-7.2mm
Weight (D) 0.0625-0.075g 0.125-0.15g 0.25-0.3g 0.375-0.45g
The present inventors have conducted intensive studies and have found that a tablet can be molded by using a conventional tablet press machine, and that the tablet has the same hardness and suitable mechanical strength as those of a conventional tablet and can be disintegrated in the oral cavity in a shorter time;
the inventor conducts intensive research on auxiliary materials of the orally disintegrating tablet, the inventor selects D-mannitol powder with excellent disintegration and poor formability and D-mannitol granules with excellent formability and poor disintegration to be mixed as a filling agent, different forms of the same substance are matched with each other to obtain unexpected effects, the mechanical strength of the orally disintegrating tablet is improved, and meanwhile, the orally disintegrating tablet has proper oral disintegration, so that the orally disintegrating tablet has proper mechanical strength and disintegration; the inventor selects the filling agent, the disintegrating agent, the lubricant, the adhesive, the flavoring agent and the spice by taking compressibility, tablet appearance, weight difference, disintegration time limit in oral cavity of volunteers, dissolving particle size, taste and the like as investigation indexes, and the Mirogabalin Besillate orally disintegrating tablet is finally obtained by mutually matching the auxiliary materials, and has proper mechanical strength and disintegration;
compared with the common tablet, the miroalbin Besilate orally disintegrating tablet can reduce dysphagia, improve compliance, is suitable for special people to take medicine, and is easily accepted by the old, patients with dysphagia, certain mental diseases and patients with difficult change of bed position; and because of the selection of auxiliary materials, the taste is good, and the medicine can be directly used in the anhydrous environment; the retention phenomenon in the digestive tract is avoided, and the stimulation to the digestive tract is small; the release is fast, the absorption is fast, simultaneously, the fear of patients to bitter drugs can be relieved, the compliance is improved, and a medication choice is added for patients and clinicians; the invention has simple process and is easy to realize large-scale production; the invention has stable physicochemical property and clinical compliance.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
Detailed Description
The technical solution of the present invention will be described in detail below with reference to specific examples.
Example 1
A prescription of a Mirogabalin Besilate orally disintegrating tablet comprises the following components:
Figure BDA0002281101440000061
Figure BDA0002281101440000071
the preparation method of the miroalbalin Besilate orally disintegrating tablet comprises the following steps:
weighing half of D-mannitol according to the amount of D-mannitol in a prescription to prepare a D-mannitol aqueous solution with the mass fraction of 10 wt%, and performing spray granulation in a fluidized bed granulator to obtain D-mannitol particles with the particle size of 150-;
mixing the miroalbalin Besilate with D-mannitol particles, corn starch, crystalline cellulose and the rest D-mannitol in a cylindrical mixer for 5min, adding hydroxypropyl cellulose, sucralose, aspartame, L-menthol and 80 wt% of magnesium stearate, mixing uniformly, adding the rest magnesium stearate, mixing uniformly, then flowing into a die of a tablet press through a barrel of the cylindrical mixer under stirring, controlling the ambient relative humidity to be not more than 60%, and tabletting to obtain the miroalbalin Besilate orally disintegrating tablet, wherein the specification of the tablet is 10mg (counted by base) per tablet, the diameter is 9.1mm, the thickness is 3.4mm, and the hardness is 32N.
Example 2
A prescription of a Mirogabalin Besilate orally disintegrating tablet comprises the following components:
Figure BDA0002281101440000072
Figure BDA0002281101440000081
the preparation method of the above miroavailin Besilate orally disintegrating tablet is the same as example 1, and the tablet has the specification of 5mg (in terms of bases) per tablet, the diameter of 7.1mm, the thickness of 2.6mm and the hardness of 30N.
Example 3
A prescription of a Mirogabalin Besilate orally disintegrating tablet comprises the following components:
Figure BDA0002281101440000082
the preparation method of the miroalbalin Besilate orally disintegrating tablet comprises the following steps:
weighing half of D-mannitol according to the amount of D-mannitol in a prescription to prepare a D-mannitol aqueous solution with the mass fraction of 10 wt%, and performing spray granulation in a fluidized bed granulator to obtain D-mannitol particles with the particle size of 150-;
mixing the miroalbalin Besilate with D-mannitol particles, crystalline cellulose and the rest D-mannitol in a cylindrical mixer for 5min, adding crospovidone, sucralose, acesulfame potassium, L-menthol and 80 wt% of sodium stearyl fumarate, uniformly mixing, adding the rest sodium stearyl fumarate, uniformly mixing, then flowing into a die of a tablet press through a barrel of the cylindrical mixer under stirring, controlling the ambient relative humidity to be not more than 60%, and tabletting to obtain the miroalbalin Besilate orally disintegrating tablet, wherein the miroalbalin Besilate orally disintegrating tablet is 5mg (counted by base) per tablet, is 7.0mm in diameter, 3.4mm in thickness and 43N in hardness.
Example 4
A prescription of a Mirogabalin Besilate orally disintegrating tablet comprises the following components:
the preparation method of the above miroavailin Besilate orally disintegrating tablet is the same as that in example 3, and the miroavailin Besilate orally disintegrating tablet has a specification of 10mg (in terms of bases)/tablet, a diameter of 9.5mm, a thickness of 4.0mm and a hardness of 36N.
Example 5
A prescription of a Mirogabalin Besilate orally disintegrating tablet comprises the following components:
Figure BDA0002281101440000092
Figure BDA0002281101440000101
the preparation method of the miroalbalin Besilate orally disintegrating tablet comprises the following steps:
weighing half of D-mannitol according to the amount of D-mannitol in a prescription to prepare a D-mannitol aqueous solution with the mass fraction of 10 wt%, and performing spray granulation in a fluidized bed granulator to obtain D-mannitol particles with the particle size of 150-;
mixing the miroalbalin Besilate, D-mannitol particles and the rest D-mannitol in a cylindrical mixer for 5min, adding polyvinyl alcohol, aspartame and L-menthol, mixing uniformly, adding silicon dioxide, mixing uniformly, adding magnesium stearate, mixing uniformly, then flowing into a die of a tablet press through a charging basket of the cylindrical mixer under stirring, controlling the ambient relative humidity to be not more than 60%, and tabletting to obtain the miroalbalin Besilate orally disintegrating tablet, wherein the miroalbalin Besilate orally disintegrating tablet is 10mg (counted by base) per tablet, 9.0mm in diameter, 4.2mm in thickness and 73N in hardness.
Example 6
A prescription of a Mirogabalin Besilate orally disintegrating tablet comprises the following components:
Figure BDA0002281101440000102
Figure BDA0002281101440000111
the preparation method of the above miroavailin Besilate orally disintegrating tablet is the same as example 5, and the tablet has the specification of 5mg (in terms of bases) per tablet, the diameter of 7.0mm, the thickness of 3.4mm and the hardness of 74N.
Example 7
A prescription of a Mirogabalin Besilate orally disintegrating tablet comprises the following components:
Figure BDA0002281101440000112
the preparation method of the miroalbalin Besilate orally disintegrating tablet comprises the following steps:
weighing half of D-mannitol according to the amount of D-mannitol in a prescription to prepare a D-mannitol aqueous solution with the mass fraction of 10 wt%, and performing spray granulation in a fluidized bed granulator to obtain D-mannitol particles with the particle size of 150-;
mixing the miroalbalin Besilate, D-mannitol particles and the rest D-mannitol in a cylindrical mixer for 5min, adding croscarmellose sodium, hydroxypropyl methylcellulose acetate succinate, aspartame, L-menthol and peppermint oil, uniformly mixing, adding silicon dioxide, uniformly mixing, adding sodium stearyl fumarate, uniformly mixing, then flowing into a die of a tablet press through a barrel of the cylindrical mixer under stirring, controlling the ambient relative humidity to be not more than 60%, and tabletting to obtain the miroalbalin Besilate orally disintegrating tablet, wherein the miroalbalin Besilate orally disintegrating tablet is 10mg (counted by base) per tablet, 9.5mm in diameter, 4.15mm in thickness and 45N in hardness.
Example 8
A prescription of a Mirogabalin Besilate orally disintegrating tablet comprises the following components:
Figure BDA0002281101440000121
the preparation method of the above miroavailin Besilate orally disintegrating tablet is the same as example 7, and the tablet has a specification of 5mg (in terms of bases) per tablet, a diameter of 7.0mm, a thickness of 3.55mm and a hardness of 46N.
Example 9
A prescription of a Mirogabalin Besilate orally disintegrating tablet comprises the following components:
Figure BDA0002281101440000131
the preparation method of the miroalbalin Besilate orally disintegrating tablet comprises the following steps:
weighing half of hydroxypropyl methylcellulose according to the formula amount to prepare 10 wt% of hydroxypropyl methylcellulose aqueous solution, and performing spray granulation in a fluidized bed granulator to obtain 250 μm hydroxypropyl methylcellulose particles with the particle size of 150-;
mixing the miroavailin Besilate with hydroxypropyl methylcellulose particles, the rest hydroxypropyl methylcellulose and hydroxypropyl cellulose in a cylindrical mixer for 5min, adding powdery reduced maltose starch, trehalose, polyethylene glycol 400, titanium dioxide, ferric oxide, sucralose, saccharin sodium hydrate and L-menthol, uniformly mixing, then flowing into a die of a tablet press through a charging basket of the cylindrical mixer under stirring, controlling the relative humidity of the environment to be not more than 60%, and tabletting to obtain the miroavailin Besilate orally disintegrating tablet, wherein the miroagulate Besilate orally disintegrating tablet is 10mg (counted by base) per tablet, 21mm in length, 17mm in width, 110-.
Example 10
A preparation method and a prescription of a Mirogabalin Besilate orally disintegrating tablet are as follows:
Figure BDA0002281101440000141
the preparation method of the above miroavailin Besilate orally disintegrating tablet is the same as example 9, and the tablet has the specification of 5mg (in terms of bases) per tablet, the length of 20mm, the width of 14mm, the thickness of 80-100um and the hardness of 67N.
Example 11
A prescription of a Mirogabalin Besilate orally disintegrating tablet comprises the following components:
Figure BDA0002281101440000142
Figure BDA0002281101440000151
the preparation method of the above miroavailin Besilate orally disintegrating tablet is the same as example 9, and the tablet has a specification of 2.5mg (in terms of bases) per tablet, a length of 20mm, a width of 14mm, a thickness of 65-85um and a hardness of 71N.
Example 12
A prescription of a Mirogabalin Besilate orally disintegrating tablet comprises the following components:
Figure BDA0002281101440000152
Figure BDA0002281101440000161
the preparation method of the above miroavailin Besilate orally disintegrating tablet is the same as that of example 9, and the tablet has the specification of 15mg (in terms of bases)/tablet, the length of 22mm, the width of 15mm, the thickness of 110-.
Quality evaluation of test examples
1. Content uniformity
The method comprises the following steps: taking 1 tablet of the product, adding 15ml deionized water, dispersing and disintegrating by ultrasonic, adding methanol for dissolving, clarifying, adding methanol to prepare 0.25mg Mirogabalin Besilate per ml, filtering with a filter membrane with the aperture of 0.45 μm, discarding the former 10ml filtrate, taking the latter 10ml filtrate, adding methanol for dissolving to 50ml, shaking up to obtain the sample solution. And accurately weighing 50mg of the Mirogabalin Besilate reference substance which is pre-dried for 3 hours at 105 ℃, putting the reference substance into a 100ml measuring flask, adding methanol for dissolving and determining the solution, shaking up, accurately weighing 3ml, putting the reference substance into a 50ml measuring flask, adding methanol for diluting to a scale, and shaking up to obtain the reference substance solution. And (3) irradiating the two solutions by an ultraviolet-visible spectrophotometry, taking a dissolution medium as a blank for determination, determining absorbance at a wavelength of 350nm respectively, and calculating the content.
As a result: the content uniformity of examples 1-12 was as specified (100.4% -101.0%).
2. Disintegration time limit
The method comprises the following steps: taking one 10ml needle cylinder (with the inner diameter of 1.5cm and the outlet positioned in the middle of the lower end of the needle cylinder), sleeving a section of 2cm long rubber tube at the outlet of the lower end, clamping the rubber tube by a water stop clamp, placing and fixing the rubber tube on a dissolution instrument or a disintegration instrument, adding 2ml of water with the temperature of 37 ℃ at the upper end of the needle cylinder, immersing the lower half part of the needle cylinder into a constant-temperature circulating water bath with the temperature of 37 ℃ in the dissolution instrument or the disintegration instrument for constant temperature for 5 minutes, adding 1 tablet of the product, starting to record the disintegration time limit, observing the disintegration condition, and completely disintegrating. The syringe was removed and the water stop clip was released, allowing the solution to pass through a 30 mesh screen and all the solution should pass.
As a result: the disintegration time periods for examples 1-12 were all specified (6 determinations should all disintegrate completely within 1 minute and all pass through a 30 mesh screen).
3. Dissolution rate
Taking the product, and performing dissolution determination (paddle method).
HPLC detection conditions:
the filler of the chromatographic column is L7, the specification is 150 multiplied by 4.6mm, 5 μm; UV detector, λ 350 nm; the flow rate is 1 ml/min; the sample injection volume is 20 mul;
mobile phase a was acetonitrile: buffer (20: 80 v/v); the mobile phase B is acetonitrile: dissolving 1.96g of phosphoric acid and 0.34g of tetrabutylammonium hydrogen sulfate in 1000ml of water to obtain a buffer solution (80: 20v/v), and performing gradient elution, wherein the elution procedure is shown in Table 1
TABLE 1 mobile phase composition
Dissolution results are shown in the following table:
Figure BDA0002281101440000172
Figure BDA0002281101440000181
from the results in the table above, it can be seen that the dissolution rate of the present invention is much higher than that of the conventional tablet.
4. Stability test
The test samples of example 4 were subjected to an accelerated test after PTP-packaging at a test temperature of 40 ℃ C. + -. 1 ℃ and a test humidity of 75% RH. + -. 5% RH, and the results are shown in the following table:
the stability of the present invention is good as can be seen from the above table.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.

Claims (10)

1. The miroalbalin Besilate orally disintegrating tablet is characterized by comprising the following raw materials in percentage by weight: 5-6.5% of Mirogabalin Besilate, 70-87% of filler, 2.5-15% of disintegrant, 0-2.18% of lubricant, 0-10% of macromolecular coating agent, 0-5% of colorant, 0-10% of adhesive, 0.5-2% of flavoring agent and 0.2-2% of spice, wherein the total weight percentage of the raw materials is 100%, and the filler is at least one of D-mannitol, crystalline cellulose, corn starch, trehalose and hydroxypropyl methylcellulose.
2. The miroalbalin Besilate orally disintegrating tablet according to claim 1, characterized in that D-mannitol is a mixture of D-mannitol powder and D-mannitol granules, wherein the weight ratio of D-mannitol powder to D-mannitol granules is 1: 0.8-1.2.
3. The miroabalin Besilate orally disintegrating tablet according to claim 2, characterized in that the particle size of the D-mannitol particles is 150-250 μm, the D-mannitol powder is 150-250 mesh; preferably, 8-12 wt% of D-mannitol aqueous solution is taken for spray granulation to obtain the D-mannitol particles.
4. The miroalbalin Besilate orally disintegrating tablet according to any one of claims 1-3, wherein the hypromellose is a mixture of hypromellose powder and hypromellose particles, wherein the weight ratio of hypromellose powder to hypromellose particles is 1: 0.8-1.2; preferably, the particle size of the hydroxypropyl methylcellulose particles is 150-250 mu m, and the particle size of the hydroxypropyl methylcellulose powder is 150-250 meshes; preferably, 8-12 wt% of hydroxypropyl methylcellulose water solution is adopted for spray granulation to obtain the hydroxypropyl methylcellulose particles.
5. The miroalbalin Besilate orally disintegrating tablet according to any of claims 1 to 4, characterized in that the disintegrant is at least one of hydroxypropyl cellulose, crospovidone, croscarmellose sodium.
6. The miroalbalin Besilate orally disintegrating tablet according to any of claims 1 to 5, characterized in that the lubricant is at least one of sodium stearyl fumarate, magnesium stearate, silicon dioxide.
7. The miroalbalin Besilate orally disintegrating tablet according to any of claims 1 to 6, characterized in that the polymeric coating agent is at least one of hydroxypropyl methylcellulose acetate succinate, powdered reduced maltose starch; preferably, the colorant is at least one of titanium dioxide and iron oxide; preferably, the binder is polyethylene glycol 400 or polyvinyl alcohol.
8. The miroalbalin Besilate orally disintegrating tablet according to any of claims 1 to 7, characterized in that the flavoring agent is at least one of acesulfame potassium, sucralose, aspartame, sodium saccharin hydrate.
9. The miroalbalin Besilate orally disintegrating tablet according to any of claims 1 to 8, characterized in that the flavor is at least one of L-menthol, peppermint oil.
10. The miroalbalin Besilate orally disintegrating tablet according to any one of claims 1 to 9, characterized in that the hardness of the miroalbalin Besilate orally disintegrating tablet is not less than 30N.
CN201911141620.6A 2019-11-20 2019-11-20 Mirogabalin Besilate orally disintegrating tablet Pending CN110742868A (en)

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Application publication date: 20200204