CN113081984A

CN113081984A - Acarbose orally disintegrating tablet and preparation method thereof

Info

Publication number: CN113081984A
Application number: CN202110419903.3A
Authority: CN
Inventors: 刘宇晶
Original assignee: Beijing Sunshine Nuohe Pharmaceutical Research Co ltd
Current assignee: Beijing Sunshine Nuohe Pharmaceutical Research Co ltd
Priority date: 2021-04-19
Filing date: 2021-04-19
Publication date: 2021-07-09
Anticipated expiration: 2041-04-19
Also published as: CN113081984B

Abstract

The invention discloses an acarbose orally disintegrating tablet and a preparation method thereof. The tablet comprises the following raw materials in parts by mass: 50 parts of acarbose, 90-110 parts of mannitol, 35-40 parts of microcrystalline cellulose, 8-10 parts of crospovidone, 0.15-0.25 part of yellow ferric oxide and 0.8-1.2 parts of magnesium stearate. The preparation method comprises the following steps: 1) sieving acarbose and magnesium stearate with a 80-mesh sieve, sieving yellow ferric oxide with a 100-mesh sieve, and respectively sieving mannitol, microcrystalline cellulose and crospovidone with a 32-mesh sieve for later use; 2) weighing acarbose, mannitol, microcrystalline cellulose, crospovidone and yellow ferric oxide in the formula amount after sieving, transferring into a V-shaped mixer, mixing, and adding magnesium stearate for total mixing; 3) tabletting the mixed raw materials to obtain the tablet. The tablet is prepared by directly tabletting powder, and the acarbose orally disintegrating tablet with excellent quality is obtained by screening and optimizing a prescription and optimizing process parameters.

Description

Acarbose orally disintegrating tablet and preparation method thereof

Technical Field

The invention belongs to the field of pharmaceutical preparations, and particularly relates to an acarbose orally disintegrating tablet and a preparation method thereof.

Background

Acarbose (Acarbose), its chemical name: o-4, 6-dideoxy-4- [ [ (1S,4R,5S,6S) -4,5, 6-trihydroxy-3- (hydroxymethyl) -2-cyclohexen-1-yl ] amino ] - α -D-glucopyranosyl- (1 → 4) -O- α -D-glucopyranose- (1 → 4) -D-glucopyranose. Acarbose was developed successfully by the german bayer company and was marketed in germany in 1990.

Acarbose is mainly used for the treatment of type II diabetes. Competitively inhibits the glycoside hydrolase in the intestinal tract. Inhibit alpha glucosidase in small intestine, inhibit polysaccharide decomposition of food, and slow sugar absorption, so as to reduce postprandial hyperglycemia, and treat diabetes by matching with diet. Can be used together with other oral medicines in NIDDM (non-insulin dependent diabetes mellitus), and can also be used together with insulin for IDDM (insulin dependent diabetes mellitus) patients to effectively control diabetes.

Because of its special physical properties, acarbose is very hygroscopic and deliquescent, and becomes hard after moisture absorption, seriously affecting taste and drug efficacy, it has been shown that the stability of acarbose preparations and its moisture are closely related, and japanese patent publication (laid-open No.39340/1995) has pointed out that: when the water content of the acarbose exceeds 6 percent, the acarbose can be degraded in main components and accompanied with discoloration after being stored for 6 weeks at 60 ℃, and after the acarbose is degraded by moisture absorption, the related substances are obviously increased, and the appearance discoloration of the acarbose is also easy to cause speckles, so that the compliance of patients is reduced. The acarbose tablet has the characteristic that the main component is easy to absorb moisture, and the phenomena of increased tablet hardness and slow disintegration can also occur in the storage process.

The current common preparation method of tablets:

and (3) wet granulation: the conventional wet granulation process results in delayed disintegration and slow dissolution of the tablet. The addition of a disintegrant in wet granulation can easily result in increased moisture absorption of the tablet, and the disintegration is delayed after the sample is stored for a long time.

And (3) dry granulation: because the dry granulation tablet pressing cake needs large extrusion pressure, the tablet is easy to be reduced in disintegration performance and difficult to disintegrate under the condition that the disintegrant is not added into the tablet. The dry granulation has low yield per se, and the fine powder needs to be pressed in the dry granulator again, so that the production time is long, the working procedures are complicated, and the dry granulation is not suitable for large-scale production.

Powder direct pressing: if a powder direct compression process is adopted, the auxiliary materials have good fluidity and formability, and the selection and proportion of the auxiliary materials and the preparation process of the process need to be groped and optimized.

Disclosure of Invention

The invention aims to provide an acarbose orally disintegrating tablet and a preparation method thereof.

The acarbose orally disintegrating tablet provided by the invention comprises the following raw materials in parts by mass: 50 parts of acarbose, 90-110 parts of mannitol, 35-40 parts of microcrystalline cellulose, 8-10 parts of crospovidone, 0.15-0.25 part of yellow ferric oxide and 0.8-1.2 parts of magnesium stearate.

Further, the mannitol is mannitol 200 SD; the microcrystalline cellulose is microcrystalline cellulose 102;

the acarbose particle size 80-mesh passing rate is 100%. The particle size of the yellow ferric oxide is 100 meshes, and the passing rate of the yellow ferric oxide is 100%. The particle size of the magnesium stearate is 80 meshes, and the passing rate is 100%.

Specifically, the acarbose orally disintegrating tablet is prepared from the following raw materials in parts by mass: 50 parts of acarbose, 200SD 100 parts of mannitol, 10238.8 parts of microcrystalline cellulose, 10 parts of crospovidone, 0.2 part of yellow ferric oxide and 1.0 part of magnesium stearate.

Specifically, the acarbose orally disintegrating tablet is prepared from the following raw materials in parts by mass: 100 parts of acarbose, 200SD 160 parts of mannitol 100SD 40 parts of mannitol, 10277.6 parts of microcrystalline cellulose, 20 parts of crospovidone, 0.4 part of yellow ferric oxide and 2.0 parts of magnesium stearate.

The preparation method of the acarbose orally disintegrating tablet provided by the invention comprises the following steps:

1) sieving: sieving the acarbose and the magnesium stearate with a 80-mesh sieve respectively, sieving the yellow ferric oxide with a 100-mesh sieve, and sieving the mannitol, the microcrystalline cellulose and the crospovidone with a 32-mesh sieve respectively for later use;

2) mixing: weighing acarbose, mannitol, microcrystalline cellulose, crospovidone and yellow ferric oxide in the formula amount after sieving, transferring into a V-shaped mixer, mixing, and adding magnesium stearate for total mixing;

3) tabletting: tabletting the mixed raw materials in the step 2) to obtain the acarbose orally disintegrating tablet.

The method also comprises a step of detecting the obtained mixed raw material particles and calculating the weight to be tabletted after the step 2) and before the step 3).

Quality control standard of intermediate

In the step 2) of the method, the mixing time is 10 minutes before the magnesium stearate is added; the total mixing time after addition of magnesium stearate was 10 minutes.

In the step 3) of the method, the unit content of the acarbose in the acarbose orally disintegrating tablet is 50mg, a shallow concave die with the diameter of 9mm is adopted, and the hardness is controlled to be less than 3 kg.

In the step 3) of the method, the unit content of the acarbose in the acarbose orally disintegrating tablet is 100mg, a shallow concave die with the diameter of 12mm is adopted, and the hardness is controlled to be less than 3 kg.

Compared with the prior art, the invention has the following beneficial effects:

the acarbose orally disintegrating tablet is prepared by directly tabletting powder, and an optimal preparation method is obtained by screening and optimizing a prescription and optimizing process parameters in the preparation process, so that the acarbose orally disintegrating tablet with excellent quality is obtained. The product has better and more stable dissolution effect and higher product quality.

Drawings

FIG. 1 is a graph showing the dissolution profile in water of the orally disintegrating acarbose tablets prepared in example 1.

Fig. 2 is a dissolution profile in water of the acarbose orally disintegrating tablets prepared in example 2.

FIG. 3 is a graph showing the relationship between hardness and disintegration time in example 3.

Detailed Description

The present invention is described below with reference to specific embodiments, but the present invention is not limited thereto, and any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the scope of the present invention.

The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.

Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.

In the quantitative tests in the following examples, three replicates were set up and the results averaged.

The sources of the raw materials used in the following examples are shown in the following table:

composition (I)	Manufacturer of the product	Approved article number
			Acarbose	HEBEI HUARONG PHARMACEUTICAL Co.,Ltd.	Chinese medicine standard character H20103077
Mannitol 200SD	Rogat Co/France	Registration certificate number: f20110016
			Mannitol 100SD	Rogat Co/France	Registration certificate number: f20110011
Microcrystalline cellulose 102	Asahi Kasei Co Ltd	Registration certificate number: f20130026
			Cross-linked polyvidone	Department of Care Chemicals/Germany of Pasteur European	Registration certificate number: f20090055
Yellow iron oxide	NINGBO YIPIN BIO-TECH Co.,Ltd.	Zhe medicine standard character F20060077
			Magnesium stearate	HUZHOU ZHANWANG PHARMACEUTICAL Co.,Ltd.	Zhe medicine standard character F20060056

The main production equipment used in the following examples is as follows:

dissolution testing of the acarbose orally disintegrating tablets in the following examples was performed according to the 0931 dissolution and release test of the fourth general rule of the chinese pharmacopoeia 2015 edition. The paddle method (apparatus 2) with a stirring speed of 50rpm was used, and the dissolution media were 900mL, pH1.2 hydrochloric acid solution at 37. + -. 0.5 ℃, pH4.0 buffer solution, pH6.8 phosphate solution, and water, and the sampling points: after 3 min, 5min, 10 min, 15min, 20 min and 30min, 5ml of the solution is taken out, filtered through a 0.22 μm filter membrane, and simultaneously added with equal amount of the same-temperature solvent, and the cumulative dissolution rate is measured. The test dissolution data result is the dissolution value of 6 tablets.

The dissolution amount measuring method comprises the following steps: HPLC method;

the chromatographic conditions were as follows:

stationary phase: octadecylsilane chemically bonded silica is used as a filler;

mobile phase: phosphate buffer (taking 600mg of monopotassium phosphate and 279mg of anhydrous disodium phosphate, adding water for dissolving and diluting to 1000ml) -acetonitrile (90: 10);

flow rate: 1.0 ml/min; detection wavelength: 210 nm; column temperature: 40 ℃; sample introduction volume: 50 μ l.

Example 1 acarbose orally disintegrating tablets (50 mg standard)

The unit dose formulation of the acarbose orally disintegrating tablets consists of:

[ note 1 ] the raw materials need to be dried and pure fed.

The preparation method of the acarbose orally disintegrating tablet (5 ten thousand tablets in batch) comprises the following steps:

1) sieving: sieving acarbose and magnesium stearate with a 80-mesh sieve, sieving yellow ferric oxide with a 100-mesh sieve, and sieving mannitol 200SD, microcrystalline cellulose 102 and crospovidone with a 32-mesh sieve respectively for later use;

2) mixing: weighing the screened acarbose, mannitol 200SD, microcrystalline cellulose 102, crospovidone and ferric oxide according to the prescription amount, transferring to a V-shaped mixer, mixing for 10 minutes, adding magnesium stearate, and mixing for 10 minutes;

3) and (3) intermediate detection: detecting intermediate particles, and calculating the weight of the pressed tablet;

quality control standard of intermediate

4) Tabletting: a shallow concave die with the diameter of 9mm is adopted, the hardness is controlled to be less than 3kg, and a rotary tablet press is used for tabletting according to theoretical tablets;

5) packaging: the product is packaged by aluminum-plastic by adopting a full-automatic high-speed blister packaging machine and empirical parameters, setting the forming temperature to be 120 ℃ and the heat sealing temperature to be 200 ℃, and is sleeved with a composite film bag for sealing.

Example 2 acarbose orally disintegrating tablets (specification 100mg)

quality control standard of intermediate

4) Tabletting: a shallow concave die with the diameter of 12mm is adopted, the hardness is controlled to be less than 3kg, and a rotary tablet press is used for tabletting according to theoretical tablets;

Evaluation of Effect of preparations prepared in examples 1 and 2

The disintegration time limit detection method comprises the following steps: taking 1 tablet of the product, placing in a test tube containing 2ml of water at 37 ℃, standing for starting timing, pouring into a beaker covered with a No. 2 sieve (850 mu m +/-29 mu m, 24 meshes) after 60 seconds, and allowing all the product to pass through. The 6 pieces were tested in succession and should all pass through the screen.

The above impurities were analyzed as follows:

the measurement method of the related substances is as follows:

by high performance liquid chromatography

The instrument comprises the following steps: high performance liquid chromatograph equipped with ultraviolet detector

Chromatography column (Welch Ultimate XB-NH2 column, 250mm X4.6 mm X5 μm adapted, or equivalent in potency)

Analytical balance (sensing quantity 0.01mg)

Reagent testing: potassium dihydrogen phosphate analytical pure

Anhydrous disodium hydrogen phosphate analytical reagent

Chromatographic purification of acetonitrile

Acarbose bulk drug

Mobile phase: phosphate buffer solution (taking 600mg of potassium dihydrogen phosphate and 279mg of anhydrous disodium hydrogen phosphate, dissolving in water and diluting to 1000ml) -acetonitrile (27:73) is taken as a mobile phase

Flow rate: 2.0ml/min

Detection wavelength: 210nm

Sample introduction amount: 20 μ l

Column temperature: 35 deg.C

Operating time: 2.5 times the main peak retention time (about 70min)

Diluent agent: water (W)

System applicability solution: taking about 200mg of acarbose, placing the acarbose into a 20ml measuring flask, adding a small amount of water to dissolve the acarbose, adding 1ml of 0.1mol/L sodium hydroxide solution, uniformly mixing, standing at room temperature for 1 hour, adding 1ml of 0.1mol/L hydrochloric acid solution, diluting with water to a scale, and shaking up to obtain the acarbose.

Test solution: taking a proper amount of the fine powder (about equal to 250mg of acarbose), putting the fine powder into a 25ml measuring flask, adding a proper amount of water, shaking to dissolve, diluting with water to a scale, shaking uniformly, filtering, and taking a subsequent filtrate as a test solution; the concentration was about 20 mg/ml.

Control solution: precisely measuring 1ml of the test solution, placing the test solution in a 100ml measuring flask, diluting the test solution to a scale with water, and shaking up to obtain a control solution. The concentration was about 200. mu.g/ml.

Sample introduction and system applicability requirements are as follows: measuring 20 mul of system applicability solution, injecting into a liquid chromatograph, recording chromatogram, wherein the retention time of the degraded impurity A relative to the main peak is about 0.9, and the separation degree of the impurity A and the acarbose main peak is not less than 1.3.

Results calculation and limits: the content was calculated by a self-control method multiplied by a correction factor, and the formula is as follows, all of which should meet the corresponding limit in the table [ impurity peaks with a content of less than 0.1% are ignored, solvent peaks (chromatogram with a relative retention time of about 0.1) and mannitol peaks (chromatogram peaks with a relative retention time of about 0.24) are not included in the impurities.

In the formula: s is an impurity in a chromatogram of the test solution;

sr is the peak area of the main peak of the control solution;

f is an impurity correction factor.

The dissolution profiles of the samples of examples 1, 2 are as follows:

through inspection, the above inspection indexes of the acarbose oral disintegrating tablet with the specification of 50mg and the acarbose oral disintegrating tablet with the specification of 100mg both meet the requirements, and therefore, the prescription composition of the two specifications is established.

Investigation of mouthfeel:

the orally disintegrating tablet can be quickly disintegrated in oral cavity, has no gravel feeling, good taste, is easy to swallow, has no irritation to oral mucosa, and is considered for the purpose of taste. After the volunteers rinse the mouth with clear water, one piece of the mouth is placed in the middle of the tongue, the oral cavity is naturally closed, the tongue is kept still, and after complete disintegration, the test object in the oral cavity is spitted out and rinsed, so that the mouth feel is taught.

	Specification 50mg	Specification 100mg
			Volunteer 1	Sweet taste and no grit feeling	Sweet taste and no grit feeling
Volunteer 2	Sweet taste and no grit feeling	Sweet taste and no grit feeling
			Volunteer 3	Sweet taste and no grit feeling	Sweet taste and no grit feeling
Volunteer 4	Sweet taste and no grit feeling	Sweet taste and no grit feeling
			Volunteer
5	Sweet taste and no grit feeling	Sweet taste and no grit feeling

The taste is sweet without gritty feeling and is good through testing medicines and telling the taste of a plurality of volunteers, so that the product can have good taste for patients without adding other flavoring agents, thereby being convenient to take.

To further verify the formulation process of the products prepared in examples 1 and 2, the in vitro dissolution behavior and related substances were compared between the acarbose orally disintegrating tablets prepared in examples 1 and 2 and the reference formulation.

Reference formulation:

preparing a self-prepared product:

specification 50mg	Batch number	20190701	20191001	20191002	20191003
						Specification 100mg	Batch number	20190702	20191004	20191005	20191006

(1) Comparison of dissolution behavior of self-prepared product and reference preparation in different dissolution media

Dissolution conditions:

dissolution medium: 900ml of water, pH1.2 hydrochloric acid solution, pH4.0 buffer solution and pH6.8 buffer solution are used as dissolution media; the method comprises the following steps: XC second law-paddle method which is an annex of the second part of the Chinese pharmacopoeia 2010 edition;

rotating speed: 50 revolutions per minute;

sampling points are as follows: after 3 min, 5min, 10 min, 15min, 20 min and 30min, 5ml of the solution is filtered through a 0.22 μm filter membrane and simultaneously added with equal amount of isothermal solvent.

The determination method comprises the following steps: HPLC method.

The standard 50mg and 100mg acarbose orally disintegrating tablets are prepared by comparing the results of the dissolution curve measurement of a self-prepared product and a reference preparation in four media:

through detection, the dissolution rates of the self-made product and the reference preparation reach more than 85% within 15min, and according to related guiding principles, F2 factor is not calculated, which indicates that the dissolution curves of the self-made sample and the reference preparation are similar.

(2) Comparison of related substances

The related substances are determined by the same method as the above

As a result:

the results of comparing the self-preparation with the reference preparation show impurity A, B, C, D, E, F, G, H, unknown single impurity, total impurity, and are substantially consistent with the impurity spectrum of the reference preparation.

Example 3 examination of adjuvants and amounts in the formulation

(1) Investigation of the Filler

The product primarily draws up a powder direct-compression process, selects 200SD model with slightly larger particle size and better fluidity for the mannitol, simultaneously considers the combined use of other fillers, and primarily screens the effects of microcrystalline cellulose 102, sorbitol and xylitol in the prescription. The hydroxypropyl cellulose adopts a low-substitution type as a disintegrating agent, the yellow ferric oxide and the magnesium stearate are added according to a conventional amount, and the compressibility and disintegration time limit of the tablet are taken as main investigation indexes, and the method comprises the following steps:

note: - -is not added.

The preparation process comprises the following steps:

1. sieving acarbose and magnesium stearate with 80 mesh sieve, sieving yellow ferric oxide with 100 mesh sieve, and sieving mannitol 200SD, microcrystalline cellulose 102, sorbitol, xylitol and polyvinylpolypyrrolidone with 32 mesh sieve respectively;

2. weighing acarbose, mannitol 200SD, microcrystalline cellulose 102, sorbitol, xylitol, low-substituted hydroxypropyl cellulose, yellow ferric oxide and magnesium stearate according to the prescription amount, and fully and uniformly mixing in a self-sealing bag;

3. tabletting by adopting a shallow concave mould with the diameter of 9mm according to the theoretical tablet weight;

4. and (6) detecting.

	Test 1	Test 2	Test 3	Test 4
					Traits	Yellow tablet	Yellow tablet	Yellow tablet	Yellow tablet
Compressibility	Is preferably used	Is preferably used	Is preferably used	Is preferably used
					Hardness (kg)	2.52	2.57	2.70	2.56
Disintegration time limit	Fail to be qualified	Small amount of failed	Fail to be qualified	Fail to be qualified

The disintegration time limit detection method comprises the following steps:

taking 1 tablet of the product, placing in a test tube containing 2ml of water at 37 ℃, standing for starting timing, pouring into a beaker covered with a No. 2 sieve (850 mu m +/-29 mu m, 24 meshes) after 60 seconds, and allowing all the product to pass through. The 6 pieces were tested in succession and should all pass through the screen.

Through investigation, the compressibility of each test granule tablet is better by using the filler. Under the same tablet hardness, the disintegration time is different, when xylitol and sorbitol are used as fillers, the tablet is corroded and dispersed, and the speed is lower; when mannitol is used alone, and microcrystalline cellulose 102 is used in combination, the disintegration rate is improved, but the effect is best when microcrystalline cellulose 102 is used in combination, for which reason mannitol 200SD and microcrystalline cellulose 102 are tentatively used in combination as fillers.

The thickness of each of the above test tablets was slightly thicker, and for this reason we considered reducing the tablet weight by an equal ratio to improve the disintegration time of the tablets. Meanwhile, the colors of all the tests are yellow tablets, and are darker than the photographs of reference preparations published by PMDA, so that the dosage of the yellow iron oxide needs to be considered.

(2) Examination of colorant amount

In order to improve the disintegration time of the tablet, the weight of a 50mg standard tablet is adjusted to 200mg, and the weight of a 100mg standard tablet is adjusted to 400mg, and the powder direct compression process is still adopted. In order to make the appearance color of the self-prepared product close to that of the reference preparation, the dosage of the yellow ferric oxide is considered, and the dosage of the yellow ferric oxide is set to be 0.3 percent, 0.2 percent and 0.1 percent of the total tablet weight, the dosage of the fixed mannitol is 50 percent, the dosage of the low-substituted hydroxypropyl cellulose is 10 percent and the dosage of the magnesium stearate is 0.5 percent, and the microcrystalline cellulose is used for supplementing the theoretical tablet weight.

The method mainly takes the appearance color as a main investigation index, and comprises the following steps:

the preparation process comprises the following steps:

1. sieving acarbose and magnesium stearate with a 80-mesh sieve, sieving yellow ferric oxide with a 100-mesh sieve, and sieving mannitol 200SD, microcrystalline cellulose 102 and low-substituted hydroxypropyl cellulose with a 32-mesh sieve respectively for later use;

2. weighing acarbose, mannitol 200SD, microcrystalline cellulose 102, low-substituted hydroxypropyl cellulose and yellow ferric oxide according to the prescription amount, fully mixing in a self-sealing bag, and then adding magnesium stearate to be uniformly mixed;

4. and (6) detecting.

	Test 1	Test 2	Test 3
				Traits	Yellow tablet	Light yellow tablet	Light yellow tablet

According to the investigation, the color gradually becomes lighter along with the reduction of the dosage of the yellow ferric oxide, and through comparison, when the dosage of the yellow ferric oxide is 0.1 percent, the color is the closest to a reference preparation, and therefore, the dosage of the yellow ferric oxide serving as a coloring agent of the product is temporarily 0.1 percent. The tablet weight is adjusted to suit the tablet thickness, and the adjusted tablet weight will be used in the following examination.

(3) Investigation of the amount of Filler

After determining that the filler is mannitol 200SD and microcrystalline cellulose 102, the dosage ratio is considered. Firstly, setting the dosage of mannitol as 40%, 50% and 60%, fixing the dosage of other raw and auxiliary materials, and supplementing microcrystalline cellulose 102 to the theoretical weight of the tablet. Mainly takes the compressibility and disintegration time limit of the tablet as the investigation indexes, and the specific indexes are as follows:

the preparation process comprises the following steps:

4. and (6) detecting.

	Test 1	Test 2	Test 3
				Traits	Light yellow tablet	Light yellow tablet	Light yellow tablet
Compressibility	Is preferably used	Is preferably used	Is preferably used
				Hardness (kg)	2.55	2.53	2.56
Disintegration time limit	Small amount of failed	Small amount of failed	Small amount of failed

The disintegration time limit detection method comprises the following steps: the same as in "examination of fillers".

Through investigation, the mannitol 200SD and the microcrystalline cellulose 102 are mixed according to the proportion, and the compressibility of the tablet is good; the disintegration time limit detection is not qualified, but no obvious difference is seen; under the condition of the same hardness range, the tablet is difficult to disintegrate again after being disintegrated into large blocks with the increase of the dosage of 200SD of mannitol; considering that mannitol has a good taste, the dosage of mannitol 200SD is temporarily 50% and microcrystalline cellulose 102 is added to theoretical tablet weight.

(4) Investigation of disintegrants in formulations

In order to enable the product to have a better disintegration effect, the study of the disintegrating agent is carried out, crospovidone, carboxymethyl starch sodium and croscarmellose sodium are primarily selected for study, the preset dosage is 8%, the disintegration time limit is mainly used as a study index, and the concrete steps are as follows:

note: - -is not added.

The preparation process comprises the following steps:

1. sieving acarbose and magnesium stearate with 80 mesh sieve, sieving ferric oxide with 100 mesh sieve, and sieving mannitol 200SD, microcrystalline cellulose 102, crospovidone, carboxymethyl starch sodium, and croscarmellose sodium with 32 mesh sieve;

2. weighing acarbose, mannitol 200SD, microcrystalline cellulose 102, crospovidone or sodium carboxymethyl starch or sodium croscarmellose and yellow ferric oxide according to the prescription amount, fully mixing in a self-sealing bag, adding magnesium stearate, and mixing uniformly;

4. and (6) detecting.

	Test 1	Test 2	Test 3
				Traits	Light yellow tablet	Light yellow tablet	Light yellow tablet
Hardness (kg)	2.54	2.55	2.53
				Disintegration time limit	All pass through	Small amount of failed	Small amount of failed

Through investigation, under the condition that the components of the prescription are in the same hardness range, the disintegration effect of the crospovidone is obviously superior to that of carboxymethyl starch sodium and croscarmellose sodium, and therefore the crospovidone is tentatively used as the disintegrant of the product.

(5) Investigation of disintegrant dosage

To determine the optimum amount of crospovidone, we examined its amount. Setting the usage amount of the crospovidone to be 3%, 5% and 8%, fixing the usage amount of other raw and auxiliary materials, and supplementing microcrystalline cellulose 102 to the theoretical weight of the tablet. The disintegration time limit of the tablet is mainly taken as a survey index, and the method comprises the following specific steps:

the preparation process comprises the following steps:

1. sieving acarbose and magnesium stearate with a 80-mesh sieve, sieving yellow ferric oxide with a 100-mesh sieve, and sieving mannitol 200SD, microcrystalline cellulose 102 and crospovidone with a 32-mesh sieve respectively for later use;

2. weighing acarbose, mannitol 200SD, microcrystalline cellulose 102, crospovidone and yellow ferric oxide according to the prescription amount, fully mixing in a self-sealing bag, and then adding magnesium stearate to be uniformly mixed;

4. and (6) detecting.

	Test 1	Test 2	Test 3
				Traits	Light yellow tablet	Light yellow tablet	Light yellow tablet
Hardness (kg)	2.53	2.55	2.51
				Disintegration Rate (second)	8.57	8.14	7.56
Disintegration time limit	All pass through	All pass through	All pass through

Through investigation, under the condition that the components of the prescription are in the same hardness range, when the usage amounts of the crospovidone are 3%, 5% and 8%, the disintegration time limit of the product meets the requirement, but the 5% and 8% usage amounts have no obvious difference compared with the disintegration speed, but the disintegration speed is higher than 3%, so that when the usage amount reaches 5%, the optimal usage amount of the product is reached, and therefore, the usage amount of the crospovidone is tentatively 5%.

(6) Inspection of sieving mesh number of raw and auxiliary materials

In order to ensure that the acarbose orally disintegrating tablet has no coarse sand feeling after being disintegrated in the oral cavity and ensure the flowability of granules, the sieving number of the raw and auxiliary materials of the acarbose orally disintegrating tablet is investigated. The product is an orally disintegrating tablet, and the finer the particles after disintegration, the better the taste, but the product is a powder direct-pressing process, and the flowability of the particles is not facilitated if the powder is too fine.

Based on that all the raw and auxiliary materials do not damage the original particle size, the screen mesh size capable of passing through is selected, and the screening investigation of 32 meshes, 50 meshes, 80 meshes and 100 meshes is preliminarily carried out, and the method specifically comprises the following steps:

note: - - -is not investigated.

According to investigation, the acarbose, the yellow ferric oxide and the magnesium stearate can all pass through a sieve of 80 meshes and a sieve of 100 meshes, so that the materials, particularly the yellow ferric oxide, are more fine, the acarbose and the magnesium stearate are arranged to pass through the sieve of 80 meshes, and the yellow ferric oxide passes through the sieve of 100 meshes; the microcrystalline cellulose 102 can completely pass through a 32-mesh sieve and a 50-mesh sieve, the mannitol 200SD and the crospovidone can completely pass through the 32-mesh sieve, and the 32-mesh sieve is arranged for reducing the working procedures. When the disintegration time is examined, the product is disintegrated by passing through a No. 2 sieve (850 mu m +/-29 mu m, 24 meshes), and therefore, the sieve mesh number of the materials can meet the requirement even if the material particles are not continuously dispersed and insoluble after meeting water.

(7) Examination of particle flowability

Preparing a batch of particles according to the determined prescription and preparation process, and inspecting according to an angle of repose inspection method.

The pellets fell freely from the funnel to form a stack on a disk of radius r, and tan α ═ h/r when the height of the stack was measured as h. The method comprises the following specific steps:

investigation item	High (cm)	Radius (cm)	Angle of repose (degree)
				Test 1	2.50	3.00	39.81
Test 2	2.40	3.00	38.66
				Test 3	2.40	3.00	38.66
Average (degree)	2.43	3.00	39.04

Through investigation, the product has an average angle of repose less than 40 degrees and good particle fluidity, and is suitable for being required by the filling of a high-speed tablet press in actual large-scale production.

(8) Investigation of tablet hardness Range

The product is an orally disintegrating tablet, the disintegration time is an important investigation index, and the tablet hardness has direct influence on the disintegration time, so the investigation of the tablet hardness range is carried out.

Preparing a batch of granules according to a determined prescription process, tabletting, designing the hardness of the tablets to be 1.5kg, 2kg, 3kg, 4kg, 5kg and 6kg, and investigating corresponding disintegration time limit to accurately evaluate the disintegration speed of each experiment.

The disintegration time of the tablet is detected by a time-limit instrument and is timed by a stopwatch, and the specific steps are as follows:

	test 1	Test 2	Test 3	Test 4	Test 5	Test 6
							Design hardness (kg)	1.50	2.00	3.00	4.00	5.00	6.00
Hardness test (kg)	1.50	2.12	3.01	4.02	5.04	5.97
							Disintegration time limit (second)	8.93	9.08	9.32	11.18	13.97	16.00

The disintegration time limit detection method comprises the following steps: an annex XA disintegration time limit detection method in Chinese pharmacopoeia 2015 edition.

As can be seen from FIG. 3, when the hardness of the tablet is 1.5kg to 3kg, the disintegration time is maintained at about 10 seconds, but when the hardness is increased to 4kg to 6kg, there is a marked sharp increase in disintegration time.

Meanwhile, the test is subjected to a static disintegration test, and the detection method is as follows: taking 1 tablet of the product, placing in a test tube containing 2ml of water of 37 ℃, standing for timing, pouring into a beaker covered with a No. 2 sieve (850 mu m +/-29 mu m, 24 meshes) after 60 seconds, and allowing all the product to pass through. The 6 pieces were tested in succession and should all pass through the screen.

Test 1

Test 2

Test 3

Test 4

Test 5

Test 6

Design hardness (kg)

1.50

2.00

3.00

4.00

5.00

6.00

Disintegration time limit

Qualified

Fail to be qualified

Through static disintegration test detection, when the hardness reaches above 3kg, the disintegration time does not meet the requirement, when the hardness reaches 3kg, the disintegration time meets the requirement, but may be a critical point, and in order to guarantee the quality, the upper limit of the hardness is 3kg when tabletting.

Claims

1. The acarbose orally disintegrating tablet comprises the following raw materials in parts by mass: 50 parts of acarbose, 90-110 parts of mannitol, 35-40 parts of microcrystalline cellulose, 8-10 parts of crospovidone, 0.15-0.25 part of yellow ferric oxide and 0.8-1.2 parts of magnesium stearate.

2. The acarbose orally disintegrating tablet according to claim 1, characterized in that: the mannitol is mannitol 200 SD.

3. The acarbose orally disintegrating tablet according to claim 1 or 2, characterized in that: the microcrystalline cellulose is microcrystalline cellulose 102.

4. The acarbose orally disintegrating tablet according to any one of claims 1 to 3, characterized in that: the particle size of the acarbose is 80 meshes, and the passing rate is 100%; the particle size of the yellow ferric oxide is 100 meshes, and the passing rate of the yellow ferric oxide is 100%; the particle size of the magnesium stearate is 80 meshes, and the passing rate is 100%.

5. The acarbose orally disintegrating tablet according to any one of claims 1 to 4, characterized in that: the acarbose orally disintegrating tablet comprises the following components in unit dose: 50mg of acarbose, 200SD 100mg of mannitol, 10238.8 mg of microcrystalline cellulose, 10mg of crospovidone, 0.2mg of yellow ferric oxide and 1.0mg of magnesium stearate.

6. The acarbose orally disintegrating tablet according to any one of claims 1 to 4, characterized in that: the acarbose orally disintegrating tablet comprises the following components in unit dose: acarbose 100mg, mannitol 200SD 160mg, mannitol 100SD 40mg, microcrystalline cellulose 10277.6 mg, crospovidone 20mg, yellow ferric oxide 0.4mg, and magnesium stearate 2.0 mg.

7. A process for the preparation of an acarbose orally disintegrating tablet according to any of claims 1 to 6, comprising the steps of:

8. The method of claim 7, wherein: in the step 2), the mixing time is 10 minutes before adding magnesium stearate; the total mixing time after addition of magnesium stearate was 10 minutes.

9. The method of claim 7, wherein: in the step 3), the content of the acarbose in the acarbose orally disintegrating tablet is 50mg, a shallow concave die with the diameter of 9mm is adopted, and the hardness is controlled to be less than 3 kg.

10. The method of claim 7, wherein: in the step 3), the content of the acarbose in the acarbose orally disintegrating tablet is 100mg, a shallow concave die with the diameter of 12mm is adopted, and the hardness is controlled to be less than 3 kg.