Levothyroxine sodium orally disintegrating micro-tablet and preparation method thereof

Abstract

The embodiment of the invention discloses a levothyroxine sodium orally disintegrating micro-tablet and a preparation method thereof. The levothyroxine sodium orally disintegrating micro-tablet comprises the following components in percentage by weight: 0.24% of levothyroxine sodium, 86%-93% of a diluent, 7%-15% of a super disintegrating agent, 0.2%-0.45% of a flow aid, 0.5%-1% of a lubricant and 0.025%-0.1% of a flavoring agent. The orally disintegrating micro-tablet provided by the invention has better dissolution and disintegration performance, does not need to be chewed and taken after being mixed with water, has good mouth feel, is beneficial to improving the oral discomfort when the medicine is taken, and improves the medicine taking compliance of children and patients with dysphagia. The orally disintegrating micro-tablet is prepared by mixing with an equivalent progressive increase method, the content is uniform, the content uniformity of the orally disintegrating micro-tablet is ensured, the method is simple, and industrial production can be realized.

Description

Technical Field

[0001] The embodiments of the present invention relate to the technical field of pharmaceutical preparations, and in particular to a levothyroxine sodium orally disintegrating microtablet and a preparation method thereof. Background Art

[0002] Orally disintegrating mini-tablets are a new dosage form of mini-tablets, which have the advantages of both solid and liquid preparations, good stability, easy to carry, easy to swallow, fast absorption and quick onset, flexible dosage, and can significantly improve patient compliance. They are mainly used for children, the elderly and patients with dysphagia. Orally disintegrating mini-tablets have the following main characteristics:

[0003] ① Tablet diameter ≤3mm;

[0004] ② It can disintegrate quickly in the mouth. According to the requirements of the China National Medical Products Administration (NMPA), the disintegration time is less than 60s;

[0005] ③ Take it orally without drinking water, which is easy to swallow;

[0006] ④It has robust mechanical properties and the drug dosage is uniform and accurate;

[0007] ⑤Has good taste.

[0008] Levothyroxine Sodium is a sodium salt of tetraiodothyronine (T4) with the structural formula as follows: 15 H 10 I4NNaO4·nH2O, molecular weight 798.86 (n=0), is off-white to light brown powder or crystalline powder, odorless, slightly soluble in ethanol, and almost insoluble in water. Levothyroxine sodium can be used as the first choice drug for thyroid hormone replacement therapy. It is converted into triiodothyronine in the body and its activity is enhanced. It has the effects of maintaining normal growth and development of the human body, promoting metabolism, increasing heat production and enhancing sympathetic function. Levothyroxine sodium is clinically suitable for long-term replacement therapy of congenital hypothyroidism (cretinism) and hypothyroidism caused by various reasons in children and adults. It can also be used for simple goiter, chronic lymphocytic thyroiditis, and suppression (and replacement) therapy after thyroid surgery.

[0009]

[0010] Through the query of the database of the website of the State Drug Administration, the US FDA and the Japanese Drug Administration, the currently marketed levothyroxine sodium drugs include injection powder, tablets, solution, and soft capsules. The drug dosage form is still mainly tablets, with many specifications, but it still cannot meet the problem of drug dosing. It is necessary to formulate individualized therapeutic doses according to the actual situation of individuals. Secondly, the therapeutic index of levothyroxine sodium is narrow, and uneven mixing may occur during the material mixing process. Summary of the invention

[0011] To this end, the present invention adopts an equal amount incremental method to mix and obtain orally disintegrating microtablets with uniform content, which have the advantages of oral solid preparations and liquid preparations: 1. The dosage can be accurately controlled to experiment with individualized dosage plans; 2. It improves the problem of children having difficulty swallowing ordinary tablets and capsules; 3. It has good stability of solid preparations, is convenient for transportation and storage, and does not require the addition of stabilizers and preservatives; 4. The drug has a high degree of dispersion, which improves the bioavailability of the drug, and at the same time can overcome the local irritation caused by excessive local drug concentration and reduce the risk of sudden release of the drug; 5. It is less affected by the gastric emptying rate, and the intra-individual and inter-individual differences in bioavailability are small; 6. It is widely applicable to the population and can be used for children, the elderly, and patients with dysphagia; 7. The preparation method is simple and can be industrialized.

[0012] In order to achieve the above purpose, the embodiment of the present invention provides the following technical solutions:

[0013] According to a first aspect of an embodiment of the present invention, the present invention provides a sodium levothyroxine orally disintegrating microtablet, which comprises, by weight percentage, 0.24% sodium levothyroxine, 86% to 93% diluent, 7% to 15% super disintegrant, 0.2% to 0.45% glidant, 0.5% to 1% lubricant and 0.025% to 0.1% flavoring agent;

[0014] The diluent is selected from one or more of mannitol, lactose, microcrystalline cellulose, Microcelac100 (lactose microcrystalline cellulose co-processed excipient), and Starlac (starch lactose complex);

[0015] The super disintegrant is selected from one or more of sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, and cross-linked polyvinylpyrrolidone;

[0016] The glidant is selected from one or both of silicon dioxide and colloidal silicon dioxide;

[0017] The lubricant is selected from one or both of magnesium stearate and sodium stearyl fumarate;

[0018] The flavoring agent is selected from one or more of aspartame, sucralose and essence.

[0019] Furthermore, the diluent consists of mannitol and lactose in a mass ratio of 1:2.5-3.

[0020] Furthermore, the super disintegrant is cross-linked sodium carboxymethyl cellulose.

[0021] Furthermore, the glidant is colloidal silicon dioxide.

[0022] Furthermore, the lubricant is sodium stearyl fumarate.

[0023] Furthermore, the flavoring agent consists of sucralose and essence.

[0024] Furthermore, the levothyroxine sodium orally disintegrating microtablets include 0.24% levothyroxine sodium, 86.5% to 92.5% diluent, 9% to 13% super disintegrant, 0.25% to 0.3% glidant, 0.6% to 0.8% lubricant and 0.025% to 0.1% flavoring agent.

[0025] Furthermore, the levothyroxine sodium orally disintegrating microtablets include 0.24% of levothyroxine sodium, 87.48% of a diluent, 11.22% of a super disintegrant, 0.26% of a glidant, 0.7% of a lubricant, and 0.1% of a flavoring agent.

[0026] According to a second aspect of an embodiment of the present invention, the present invention provides a method for preparing the levothyroxine sodium orally disintegrating microtablets as described in any one of the above items, the method comprising the following steps:

[0027] (1) Pretreatment: Pass the diluent, super disintegrant, glidant, lubricant and flavoring agent through a 40-mesh sieve to remove lumps and set aside;

[0028] (2) Mixing by adding equal amounts: Weigh the prescribed amount of the main drug, the glidant and the equal amount of the diluent in a ziplock bag and mix them thoroughly. Then, add the diluent, disintegrant and flavoring agent in the same amount as the material in the ziplock bag in turn, mix them in small amounts and multiple times to obtain a premixed material, then add the lubricant and mix them thoroughly to obtain a total mixed material.

[0029] (3) Tablet pressing: The total mixed material is pressed into micro-tablets with a diameter of 3 mm using a micro punch, and the hardness of the micro-tablets is controlled to be 25 to 45N.

[0030] The embodiments of the present invention have the following advantages:

[0031] The orally disintegrating microtablets provided by the present invention have good dissolution and disintegration properties, do not need to be chewed or taken with water, and have a good mouthfeel, which helps to improve the oral discomfort when taking the drug and improve the medication compliance of children and patients with dysphagia.

[0032] The invention adopts the equal amount incremental mixing method to prepare the orally disintegrating microtablets, and the content is uniform, thereby ensuring the content uniformity of the orally disintegrating microtablets. The method of the invention is simple and can realize industrialized production. DETAILED DESCRIPTION

[0033] The following is a description of the implementation of the present invention by specific embodiments. People familiar with the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0034] In the following contents, all percentages involved are calculated by weight unless otherwise specified.

[0035] The main and auxiliary materials involved were purchased from commercial sources. The selected auxiliary materials were purchased from the following companies but not limited to these companies: Meggle, Roquette, BASF, Sensient, Merck, Evonik, Anhui Shanhe Pharmaceutical Excipients Co., Ltd., and Jiangsu Daoning Pharmaceutical Co., Ltd.

[0036] Except for disintegration time and taste evaluation, the test methods of other evaluation indicators such as friability, content uniformity, and appearance of plain tablets are all checked in accordance with the 2020 edition of the Chinese Pharmacopoeia. Among them, the test methods for disintegration time, taste evaluation, and powder flowability are as follows:

[0037] Disintegration time: According to the "Minutes of the Dosage Form Characteristics and Quality Control Meeting of Orally Disintegrating Tablets" issued by the CDE Review Department IV in 2003, a static method is proposed with a disintegration time of less than one minute. Water is the preferred medium and the amount should be less than 2 ml. The temperature is 37°C.

[0038] Taste evaluation: Six volunteers were used to conduct an adult oral trial to evaluate the taste of the tablets based on their subjective feelings after taking the orally disintegrating microtablets. The taste was evaluated from three aspects: smell, taste, and grittiness.

[0039] Powder fluidity: Three commonly used methods of expression are angle of repose, Carr index and Hausner ratio.

[0040] (1) Determination of the angle of repose: The angle of repose refers to the maximum angle formed by the free inclined plane formed by the accumulation of powder and the horizontal plane. The smaller the angle of repose, the better the fluidity. This paper adopts the fixed funnel method for measurement. First, three funnels are fixed on the iron frame and connected in series from top to bottom. The bottom funnel mouth is fixed about 4 cm above the horizontal scale plate. Then the auxiliary materials are poured into the top funnel to make the particles slowly slide along the walls of each funnel. Pour slowly to avoid the powder blocking the funnel mouth until the tip of the conical powder pile formed on the scale plate just touches the funnel mouth. Stop pouring the particles and measure the particle cone radius r and cone height h. The calculation formula of the angle of repose α (°) is as follows.

[0041] tanα=h / r

[0042] (2) Bulk density determination: Weigh a certain mass m (g) of auxiliary material, put it into a dry measuring cylinder, shake it gently to make it evenly distributed, read the volume V (mL) near the scale, and calculate the bulk density ρ. 堆 (g / mL), and the calculation formula is as follows.

[0043] ρ 堆 =m / V 松

[0044] Tap density: The density of a powder measured after regular vibration or tapping, i.e., tap density ρ 实 (tap density).

[0045] ρ 实 =m / V 实

[0046] Carr index (compression degree C) = 100*[(ρ 实 -ρ 堆 ) / ρ 实 ]

[0047] Hausner ratio = ρ 实 / ρ 堆

[0048] The powder evaluation indicators are shown in Table 1 below.

[0049] Table 1

[0050] Liquidity Angle of repose(°) Compression Hausnerratio Excellent 25-30° ≤10 1.00-1.11 Good 31-35° 11-15 1.12-1.18 fair 36-40° 16-20 1.19-1.25 passable 41-45° 21-25 1.26-1.34 poor 46-55° 26-31 1.35-1.45 Very poor 56-65° 32-37 1.46-1.59 Very bad (very, very poor) ＞66° ＞38 ＞1.60

[0051] Example 1

[0052] (1) Screening of diluent

[0053] The prescriptions of Comparative Examples 1-4 and Example 1 are shown in Table 2 below.

[0054] Table 2

[0055]

[0056]

[0057] Preparation process:

[0058] Pass the diluent, super disintegrant and glidant through a 40-mesh sieve respectively to remove lumps, weigh the prescribed amount of the main drug and the sieved auxiliary materials and mix them thoroughly, finally add the prescribed amount of lubricant, mix well and press into tablets.

[0059] The evaluation index test results of the tablets of Comparative Examples 1-4 and Example 1 are shown in Table 3 below.

[0060] Table 3

[0061]

[0062] Note: Disintegration time is the average value of 6 tablets (the same below).

[0063] in conclusion:

[0064] According to the diluent screening results, the appearance of the microtablets, disintegration time, friability, and powder fluidity are comprehensively analyzed. When mannitol and Microcelac100 are used alone as diluents, not only the disintegration rate is slow, but there is also a sticking phenomenon during tableting, and the mouthfeel has a gritty feeling; when Starlac is used as a diluent, the disintegration rate is the slowest, the tableting has no sticking, and the mouthfeel has a slight gritty feeling; when mannitol and microcrystalline cellulose are used as diluents, the disintegration rate is the fastest, but there is an obvious sticking phenomenon in tableting, and the gritty feeling in the mouthfeel is serious; when mannitol and lactose are used as diluents, the disintegration time is obviously faster than using mannitol and Starlac alone, there is no sticking phenomenon, and the mouthfeel overcomes the gritty feeling brought by microcrystalline cellulose. Therefore, the diluent selection of mannitol and lactose for the oral disintegrating microtablets of levothyroxine sodium in the embodiment of the present invention is the best.

[0065] (2) Screening of disintegrants

[0066] The prescriptions of Comparative Examples 5-6 and Example 2 are shown in Table 4 below.

[0067] Table 4

[0068]

[0069] Preparation process: Same as Example 1.

[0070] The evaluation index test results of the tablets of Comparative Examples 5-6 and Example 2 are shown in Table 5 below.

[0071] Table 5

[0072] Evaluation indicators Comparative Example 5 Comparative Example 6 Example 2 Appearance The surface is complete and smooth, without sticking or punching The surface is complete and smooth, without sticking or punching The surface is complete and smooth, without sticking or punching Tablet weight difference 25.35mg±5% 24.99mg±5% 25.15mg±5% hardness 45.57N 37.24N 40.41N friability 0.11％ 0.14％ 0.16％ Disintegration time 42s 36s 28s Disintegration phenomenon Dissolved, solution is clear There is white insoluble matter Dissolved, the solution is clear Angle of repose 36.027° 34.032° 36.027°

[0073] in conclusion:

[0074] According to the disintegrant screening results, in comparison of Examples 1-2 and Comparative Examples 5-6, sodium carboxymethyl starch was used as a disintegrant, and the disintegration speed was the slowest; using cross-linked polyvinylpyrrolidone as a disintegrant, the disintegration time was shorter, but there was a small amount of white insoluble matter in the solution after disintegration; using cross-linked sodium carboxymethyl cellulose as a disintegrant, the disintegration speed was faster, and the solution after disintegration was clearer. Therefore, it is better to use cross-linked sodium carboxymethyl cellulose, and the disintegration effect of the prescription ratio of 11% is better than that of 7%, and there is no significant difference in the hardness, friability and powder flowability results of the four prescriptions.

[0075] (3) Screening of glidants and lubricants

[0076] The prescriptions of Comparative Examples 7-9 and Example 3 are shown in Table 6 below.

[0077] Table 6

[0078]

[0079] Preparation process:

[0080] Pass the diluent, super disintegrant and glidant through a 40-mesh sieve respectively to remove lumps, weigh the prescribed amount of the main drug and the sieved auxiliary materials and mix them thoroughly, finally add the prescribed amount of lubricant, mix well and press into tablets.

[0081] The evaluation index test results of the tablets of Comparative Examples 7-9 and Example 3 are shown in Table 7 below.

[0082] Table 7

[0083]

[0084]

[0085] in conclusion:

[0086] Based on the screening results of glidants and lubricants, the disintegration time, friability, powder flowability and mouth feel were comprehensively analyzed. When magnesium stearate was used as a lubricant, the orally disintegrating microtablets had a slight gritty taste. When silicon dioxide was used as a glidant, the disintegration rate was slower. The use of colloidal silicon dioxide and sodium stearyl fumarate had better effects. There was no significant difference in the hardness, friability and powder flowability results of the four prescriptions.

[0087] (4) Screening of flavor correctors

[0088] The prescriptions of Comparative Examples 10-11 and Example 4 are shown in Table 8 below.

[0089] Table 8

[0090]

[0091] Preparation process:

[0092] Separately sieve the diluent, disintegrant, glidant and flavoring agent through a 40-mesh sieve to remove lumps, weigh the prescribed amount of the main drug and the sieved auxiliary materials and mix them thoroughly, finally add the prescribed amount of lubricant, mix well and press into tablets.

[0093] The evaluation index test results of the tablets of Comparative Examples 10-11 and Example 3 are shown in Table 9 below.

[0094] Table 9

[0095]

[0096] in conclusion:

[0097] According to the results of the flavoring agent investigation, when sucralose and strawberry flavor are used as flavoring agents, the taste effect is better when the prescription ratio is 0.5%. There is no significant difference in the microtablet hardness, powder fluidity, disintegration time and friability results of the three flavoring agent ratios.

[0098] (5) Hardness screening

[0099] The prescriptions of Examples 5-7 are shown in Table 10 below.

[0100] Table 10

[0101]

[0102] Preparation process: same as Example 4.

[0103] The evaluation index test results of the tablets of Examples 5-7 are shown in Table 11 below.

[0104] Table 11

[0105]

[0106] in conclusion:

[0107] According to the hardness screening and evaluation results of orally disintegrating microtablets, the weight difference, friability and appearance of microtablets with a hardness of 30-50N all meet the requirements, and the disintegration time meets the requirements of the 2020 edition of the Chinese Pharmacopoeia, which does not exceed 60s. However, as the hardness of the microtablet increases, the disintegration slows down. Therefore, it is better to control the hardness of the microtablet to 25-45N.

[0108] (6) Preparation process screening

[0109] Example 8-9 Preparation process investigation

[0110] Different preparation processes were investigated based on the preparation prescription in Example 5. The direct tableting process and the equal amount stepwise mixing process were investigated respectively.

[0111] Preparation process 1 (direct tableting process): pass the diluent, super disintegrant, glidant and flavoring agent through a 40-mesh sieve to remove lumps, weigh the prescribed amount of the main drug and the sieved auxiliary materials and mix them thoroughly, finally add the prescribed amount of lubricant sodium stearyl fumarate, mix well and press into micro-tablets with a diameter of 3 mm.

[0112] Preparation process 2 (equal amount incremental mixing process):

[0113] (1) Pretreatment: All auxiliary materials are sieved through a 40-mesh sieve to remove lumps and set aside;

[0114] (2) Mixing by adding equal amounts: Weigh the prescribed amount of the main drug, the glidant and an equal amount of the diluent (i.e., the mass of the added diluent is the sum of the mass of the main drug and the glidant) in a ziplock bag, mix them thoroughly and evenly, then add the diluent, disintegrant and flavoring agent in equal amounts to the materials in the ziplock bag (i.e., the mass of the materials added each time is the sum of the mass of the materials in the ziplock bag), mix them evenly in small amounts and multiple times to obtain a premixed material, then add the lubricant and mix them thoroughly to obtain a total mixed material;

[0115] (3) Tablet pressing: The total mixed material is pressed into micro-tablets with a diameter of 3 mm using a micro punch, and the hardness of the micro-tablets is controlled to be 25 to 45N.

[0116] The tests and results are shown in Table 12 below.

[0117] Table 12

[0118]

[0119]

[0120] in conclusion:

[0121] According to the evaluation results of the two different preparation processes, the powder fluidity is good, the prepared microtablets are free of gravel and have moderate sweetness, and the hardness, disintegration time, brittleness and intermediate mixing uniformity also meet the requirements. The difference is that the raw and auxiliary materials are directly compressed by the conventional mixing method, and the intermediate mixing uniformity A+2.2S=12.40<15 meets the mixing requirements of the intermediates, while the intermediates obtained by the equal amount incremental mixing method have better mixing uniformity, A+2.2S=4.87<12.40, and the mixing effect is better than the conventional mixing method. This may be due to the narrow therapeutic index of levothyroxine sodium and the low proportion of the main drug in the prescription. The equal amount incremental mixing method can better mix the main drug and the auxiliary materials. Therefore, it is better to use preparation process 2, which has no complex requirements, does not require special production equipment and conditions, and has no special requirements for drug packaging, and can achieve industrial production.

[0122] Although the present invention has been described in detail above by general description and specific embodiments, it is obvious to those skilled in the art that some modifications or improvements can be made to the present invention. Therefore, these modifications or improvements made without departing from the spirit of the present invention all belong to the scope of protection claimed by the present invention.

Claims

1. A levothyroxine sodium orally disintegrating microtablet, characterized in that: The levothyroxine sodium orally disintegrating microtablets include, by weight percentage, 0.24% of levothyroxine sodium, 86% to 93% of a diluent, 7% to 15% of a super disintegrant, 0.2% to 0.45% of a glidant, 0.5% to 1% of a lubricant, and 0.025% to 0.1% of a flavoring agent; The diluent is selected from one or more of mannitol, lactose, microcrystalline cellulose, Microcelac100, and Starlac; The super disintegrant is selected from one or more of sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, and cross-linked polyvinylpyrrolidone; The glidant is selected from one or both of silicon dioxide and colloidal silicon dioxide; The lubricant is selected from one or both of magnesium stearate and sodium stearyl fumarate; The flavoring agent is selected from one or more of aspartame, sucralose and essence.

2. The orally disintegrating microtablet of levothyroxine sodium according to claim 1, characterized in that: The diluent consists of mannitol and lactose in a mass ratio of 1:2.5-3.

3. The orally disintegrating microtablet of levothyroxine sodium according to claim 1, characterized in that: The super disintegrant is cross-linked carboxymethyl cellulose sodium.

4. The orally disintegrating microtablet of levothyroxine sodium according to claim 1, characterized in that: The glidant is colloidal silicon dioxide.

5. The orally disintegrating microtablet of levothyroxine sodium according to claim 1, characterized in that: The lubricant is sodium stearyl fumarate.

6. The orally disintegrating microtablet of levothyroxine sodium according to claim 1, characterized in that: The flavoring agent consists of sucralose and essence.

7. The orally disintegrating microtablet of levothyroxine sodium according to claim 1, characterized in that: The levothyroxine sodium orally disintegrating microtablets comprise 0.24% of levothyroxine sodium, 86.5% to 92.5% of a diluent, 9% to 13% of a super disintegrant, 0.25% to 0.3% of a glidant, 0.6% to 0.8% of a lubricant and 0.05% to 0.1% of a flavoring agent.

8. The orally disintegrating microtablet of levothyroxine sodium according to claim 1, characterized in that: The levothyroxine sodium orally disintegrating micro-tablets comprise 0.24% of levothyroxine sodium, 87.48% of a diluent, 11.22% of a super disintegrant, 0.26% of a glidant, 0.7% of a lubricant and 0.1% of a flavoring agent.

9. The method for preparing the levothyroxine sodium orally disintegrating microtablets according to any one of claims 1 to 8, characterized in that: The method comprises the following steps: (1) Pretreatment: Pass the diluent, super disintegrant, glidant, lubricant and flavoring agent through a 40-mesh sieve to remove lumps and set aside; (2) Mixing by adding equal amounts: Weigh the prescribed amount of the main drug, the glidant and the equal amount of the diluent in a ziplock bag and mix them thoroughly. Then, add the diluent, disintegrant and flavoring agent in the same amount as the material in the ziplock bag in turn, mix them in small amounts and multiple times to obtain a premixed material, then add the lubricant and mix them thoroughly to obtain a total mixed material. (3) Tablet pressing: The total mixed material is pressed into micro-tablets with a diameter of 3 mm using a micro punch, and the hardness of the micro-tablets is controlled to be 25 to 45N.

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