CN113876735B

CN113876735B - Liluzole microsphere preparation and preparation method thereof

Info

Publication number: CN113876735B
Application number: CN202111219607.5A
Authority: CN
Inventors: 吴江; 李元森
Original assignee: Longnan First People's Hospital; Shandong New Time Pharmaceutical Co Ltd
Current assignee: Longnan First People's Hospital; Shandong New Time Pharmaceutical Co Ltd
Priority date: 2021-10-20
Filing date: 2021-10-20
Publication date: 2023-05-12
Anticipated expiration: 2041-10-20
Also published as: CN113876735A

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a riluzole microsphere preparation and a preparation method thereof. According to the invention, the intermediate of the riluzole microsphere is prepared by screening the carrier material and the corresponding auxiliary materials, so that the encapsulation efficiency and the drug loading rate of the riluzole microsphere are improved, the problems of loss and deterioration of the riluzole active ingredient are solved, the stability of the drug is improved, and the dissolution rate of the drug is improved; the stabilizer and the proportion of the stabilizer and the microsphere intermediate are optimized, and the riluzole microsphere intermediate is prepared into a preparation, so that the content of related substances is reduced, and the stability of the medicine is further improved.

Description

Liluzole microsphere preparation and preparation method thereof

Technical Field

The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a riluzole microsphere preparation and a preparation method thereof.

Background

Riluzole, chemical name 2-amino-6-trifluoromethoxybenzothiazole, is useful for prolonging the life of patients with Amyotrophic Lateral Sclerosis (ALS) or for prolonging the time to develop to the need for mechanical ventilation support. Clinical trials have demonstrated that riluzole can extend survival in ALS patients.

Chinese patent CN 111437256A discloses a riluzole sustained-release oral suspension which is prepared by dispersing riluzole sustained-release microspheres in a solution containing a diluent, a flavoring agent, a suspending agent, a preservative and a pH buffer, wherein the riluzole sustained-release microspheres are prepared by dissolving riluzole in an ethyl cellulose aqueous dispersion and spray-drying the dispersion, and the solid content ratio of the riluzole to the ethyl cellulose aqueous dispersion is 1:1-1:3. The microspheres are often used as intermediate carriers of medicines and are required to be further processed to prepare preparations, so that the quality evaluation of the microspheres is necessary, and the quality evaluation of the microspheres is also required in pharmacopoeia, such as drug loading rate, encapsulation rate and the like, and the quality evaluation of microsphere intermediates is not carried out in the patent, and whether the quality of the microsphere intermediates is qualified is unknown. Amyotrophic lateral sclerosis is mainly manifested by muscular atrophy, weakness, difficulty speaking and swallowing, so that oral suspension is difficult to take for patients with severe amyotrophic lateral sclerosis.

Chinese patent CN 104606683A discloses an orally disintegrating preparation which comprises main riluzole, auxiliary materials of collagen peptide and sugar alcohol, wherein the main weight of the preparation is 3% -20%, the collagen peptide is 2% -18% and the sugar alcohol is 15% -80% of the total weight, the auxiliary materials used in the technical scheme are simple, the content of related substances of the preparation is not detected, and the stability of the riluzole is difficult to ensure.

Chinese patent CN 111821289B discloses a riluzole orally disintegrating tablet and its preparation method, which is prepared from riluzole, sodium bicarbonate, filler, disintegrating agent, lubricant and taste-modifying agent. However, the patent does not detect the stability of the orally disintegrating tablet such as the related substances, and the safety of administration cannot be ensured.

In view of the above disclosed technology, how to further reduce the content of riluzole related substances, improve stability and safety is a technical problem to be solved in the art.

Disclosure of Invention

The invention provides a riluzole microsphere intermediate and a preparation prepared from the riluzole microsphere intermediate, wherein the encapsulation rate and the drug loading rate of the riluzole microsphere are improved by optimizing drug-carrying materials and corresponding auxiliary materials, the prepared riluzole microsphere intermediate isolates light, humidity and oxygen to a certain extent, the problems of loss and deterioration of riluzole active ingredients are solved, the stability of the medicine is improved, and when the riluzole microsphere intermediate is prepared into the preparation, the proportion of a stabilizer, the stabilizer and the microsphere intermediate is optimized, the content of related substances is reduced, and the stability of the medicine is further enhanced.

Specifically, the technical scheme of the invention is as follows:

the invention provides a riluzole microsphere intermediate, which comprises riluzole, a carrier material, a coagulant, a cross-linking agent and a buffering agent.

The buffer includes buffer a and buffer B.

The components are calculated according to the weight portion ratio as follows:

further, the carrier material is selected from one or more of alginate, chitosan, amino acid, cellulose acetate titanate, ethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, starch, povidone, lactic acid-glycolic acid, polyamide, chitin and albumin; the coagulant is selected from one of glucose, sodium sulfate, potassium sulfate, ammonium sulfate, potassium thiocyanate, sodium chloride, potassium chloride, ethanol and propanol; the cross-linking agent is one of chloride, sulfate and carbonate; the buffer A is citrate buffer; the buffer B is phosphate buffer.

The coagulant is sodium sulfate; the coagulant is chloride salt, preferably calcium chloride; the carrier material is sodium alginate and starch.

Specifically, the weight ratio of the starch to the sodium alginate is 1:1-4, preferably 1:2.

The preferable weight ratio of each component is as follows:

a second object of the present invention is to provide a method for preparing riluzole microspheres, comprising the steps of:

(1) Preparing a suspension: dispersing riluzole and a carrier material in a suitable amount of water to form a suspension;

(2) Coagulation and deagglomeration: adding a buffering agent A into the suspension obtained in the step (1) to adjust the pH value to be between 5 and 7, adding a coagulant, heating to 40 and 50 ℃ to coagulate, adding water at 30 to 40 ℃ to dilute and deagglomerate, and repeating for 2 to 3 times;

(3) Curing: adding a cross-linking agent and a buffer B into the condensate obtained in the step (3), and curing at 2-10 ℃;

(4) Preparation of riluzole microspheres: washing the solidified product obtained in the step (3), filtering and drying to obtain the product.

The third object of the invention is to provide a preparation prepared from the intermediate of the riluzole microsphere and pharmaceutically acceptable auxiliary materials.

Such formulations include, but are not limited to, conventional tablets, orally disintegrating tablets, granules, capsules, pills, powders, chewable tablets, lozenges, and suspensions.

Further, pharmaceutically acceptable auxiliary materials contained in the preparation can comprise a stabilizer, a filler, a lubricant, a disintegrating agent and a binding agent.

Further, the filler is selected from one of starch, pregelatinized starch, dextrin, sucrose, lactose, microcrystalline cellulose and mannitol; the lubricant is selected from one of talcum powder, micro powder silica gel, magnesium stearate, polyethylene glycol, stearic acid, boric acid and dodecyl sulfate; the disintegrating agent is one or more selected from dry starch, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crosslinked sodium carboxymethyl cellulose, crosslinked povidone, sodium alginate and sodium bicarbonate; the stabilizer is one of amino acids, preferably alanine and alanine.

Wherein the weight ratio of the stabilizer to the riluzole microspheres is 1:5-30, preferably 1:15.

A fourth object of the present invention is to provide an orally disintegrating tablet comprising luazol microspheres.

The filler is mannitol; the lubricant is micro silica gel; the disintegrating agent is low-substituted hydroxypropyl cellulose; the stabilizer is alanine.

Specifically, the weight ratio of each component is as follows:

it is preferred that the composition is,

compared with the prior art, the invention has the beneficial effects that:

(1) The encapsulation efficiency and the drug loading rate of the riluzole microspheres are improved, the problem of loss and deterioration of the riluzole active ingredient is solved, the stability of the drug is improved, and the dissolution rate of the drug is improved by optimizing the drug loading materials and the corresponding auxiliary materials;

(2) When the riluzole microsphere intermediate is prepared into a preparation, the stabilizer and the proportion of the stabilizer and the microsphere intermediate are optimized, so that the content of related substances is reduced, and the stability of the medicine is further enhanced;

(3) The type and proportion of auxiliary materials are optimized, the orally disintegrating tablet formulation is prepared, the disintegration time limit is shortened, and the problem that other formulations are difficult to take for amyotrophic lateral sclerosis patients is solved.

Detailed Description

The present invention will be further described with reference to examples for the purpose of making the objects and technical aspects of the present invention more apparent, but the scope of the present invention is not limited to these examples, which are only for explaining the present invention. It will be understood by those skilled in the art that variations or equivalent substitutions that do not depart from the spirit of the invention are intended to be included within the scope of the invention.

Example 1: liluzole microsphere

Preparation of riluzole microspheres:

(2) Coagulation and deagglomeration: adding a buffering agent A into the suspension obtained in the step (1) to adjust the pH to be=6, adding a coagulant, heating to 45 ℃ to coagulate, adding 35 ℃ water to dilute and deagglomerate, and repeating the coagulation and deagglomeration for 3 times;

(3) Curing: adding a cross-linking agent and a buffer B (0.1 mol/l) into the condensate obtained in the step (3), and curing at 5 ℃;

Example 2: liluzole microsphere

Preparation of riluzole microspheres:

(2) Coagulation and deagglomeration: adding a buffering agent A into the suspension obtained in the step (1) to adjust the pH to be=5, adding a coagulant, heating to 40 ℃ to coagulate, adding 30 ℃ water to dilute and deagglomerate, and repeating the coagulation and deagglomeration for 3 times;

(3) Curing: adding a cross-linking agent and a buffer B (0.2 mol/l) into the condensate obtained in the step (3), and curing at 2 ℃;

Example 3: liluzole microsphere

Preparation of riluzole microspheres:

(2) Coagulation and deagglomeration: adding a buffering agent A into the suspension obtained in the step (1) to adjust the pH to be 7, adding a coagulant, heating to 50 ℃ to coagulate, adding 40 ℃ water to dilute and deagglomerate, and repeating the coagulation and deagglomeration for 3 times;

(3) Curing: adding a cross-linking agent and a buffer B (0.5 mol/l) into the condensate obtained in the step (3), and curing at 10 ℃;

Example 4: orally disintegrating tablet (1000 tablets)

The preparation method comprises the following steps:

(1) Crushing and sieving: respectively pulverizing mannitol, silica gel micropowder, low-substituted hydroxypropyl cellulose and alanine, and sieving;

(2) Mixing; placing mannitol, low-substituted hydroxypropyl cellulose, alanine and riluzole microspheres sieved in the step (1) into a mixer to mix for 5min, adding micro silica gel and continuing mixing for 10min;

(3) Granulating, drying, and tabletting.

Example 5: common sheet (1000 sheets)

The preparation method comprises the following steps:

(1) Crushing and sieving: respectively pulverizing microcrystalline cellulose, pulvis Talci, starch, and alanine, and sieving;

(2) Mixing; placing the microcrystalline cellulose, starch, alanine and riluzole microspheres sieved in the step (1) into a mixer to mix for 5min, adding talcum powder and continuing mixing for 10min;

(3) Granulating, drying, and tabletting.

Example 6: granule (1000 tablets)

The preparation method comprises the following steps:

pre-mixing riluzole microsphere, adding the crushed and sieved dextrin, magnesium stearate, crospovidone and alanine into a granulator, mixing, adding a proper amount of water, granulating, extruding, rounding and drying to obtain the final product.

Example 7: orally disintegrating tablet (1000 tablets)

The preparation method comprises the following steps:

(1) Crushing and sieving: respectively pulverizing microcrystalline cellulose, pulvis Talci, crospovidone, and alanine, and sieving;

(2) Mixing; placing the microcrystalline cellulose, the crosslinked povidone, the alanine and the riluzole microspheres which are sieved in the step (1) into a mixer to be mixed for 5min, and adding talcum powder to be mixed for 10min;

(3) Granulating, drying, and tabletting.

Example 8: orally disintegrating tablet (1000 tablets)

The preparation method comprises the following steps:

(1) Crushing and sieving: respectively pulverizing starch, magnesium stearate, sodium alginate and alanine, and sieving;

(2) Mixing; placing the starch, sodium alginate, alanine and riluzole microspheres sieved in the step (1) into a mixer to mix for 5min, adding magnesium stearate and continuing mixing for 10min;

(3) Granulating, drying, and tabletting.

Comparative example 1 riluzole microspheres

Preparation of riluzole microspheres:

Comparative example 2 riluzole microspheres

Preparation of riluzole microspheres:

(2) Coagulation and deagglomeration: adding a buffering agent A into the suspension obtained in the step (1) to adjust the pH value to be between 5 and 7, adding a coagulant, heating to 40 and 50 ℃ to coagulate, adding water at 30 to 40 ℃ to dilute and deagglomerate, and repeating the coagulation and deagglomeration for 3 times;

Comparative example 3 orally disintegrating tablets

The preparation method comprises the following steps:

(1) Crushing and sieving: respectively pulverizing mannitol, silica gel micropowder and low-substituted hydroxypropyl cellulose, and sieving;

(2) Mixing; placing mannitol, low-substituted hydroxypropyl cellulose and riluzole microspheres sieved in the step (1) into a mixer to be mixed for 5min, and adding micro powder silica gel to be mixed for 10min;

(3) Granulating, drying, and tabletting.

Comparative example 4 orally disintegrating tablets

The preparation method comprises the following steps:

(1) Crushing and sieving: respectively pulverizing mannitol, silica gel micropowder, low-substituted hydroxypropyl cellulose and poloxamer, and sieving;

(2) Mixing; placing mannitol, low-substituted hydroxypropyl cellulose, poloxamer and riluzole microspheres sieved in the step (1) into a mixer to be mixed for 5min, and adding superfine silica gel powder to be mixed for 10min;

(3) Granulating, drying, and tabletting.

Comparative example 5 riluzole microspheres

Preparation of riluzole microspheres:

Comparative example 6: orally disintegrating tablet (1000 tablets)

The preparation method comprises the following steps:

(3) Granulating, drying, and tabletting.

Verification embodiment

1. Drug loading rate

The drug loading is the mass percentage of the drugs contained in the microcapsule and the microsphere.

The calculation formula of the drug loading is as follows:

drug loading = amount of drug contained in microcapsule or microsphere/total amount of microcapsule or microsphere x 100%

Table 1 drug loading of riluzole microsphere examples and comparative examples

	Drug loading (%)
		Example 1	92.36
Example 2	90.67
		Example 3	90.89
Comparative example 1	71.43
		Comparative example 2	79.37
Comparative example 5	85.11

2. Encapsulation efficiency

The encapsulation efficiency refers to the mass percentage of the drug in the microsphere to the theoretical dosage, and is an important index for considering the good or bad of the drug microencapsulation process.

The encapsulation efficiency is calculated as follows:

encapsulation efficiency = amount encapsulated in system/total amount of encapsulated and unencapsulated in system x 100%

=1-unencapsulated drug amount in liquid medium/total drug amount encapsulated and unencapsulated in system×100%

The encapsulation efficiency generally must not be lower than 80%.

Table 2 encapsulation efficiency of riluzole microsphere examples and comparative examples

	Encapsulation efficiency (%)
		Example 1	93.14
Example 2	89.94
		Example 3	90.08
Comparative example 1	65.71
		Comparative example 2	75.32
Comparative example 5	79.64

From the measurement results of the drug loading and the encapsulation efficiency of the microspheres in table 1 and table 2, the types and the collocation of the carrier material and the curing agent and the proportion of the drug loading material to the drug have great influence on the drug loading and the encapsulation efficiency of the microspheres.

3. Drug release rate

The dissolution and release were measured by the dissolution and release measurement method (general rule 0931, second method).

Dissolution conditions: 900ml of 0.1mol/L hydrochloric acid solution is taken as a dissolution medium, the rotating speed is 50 revolutions per minute, the operation is operated according to law, and sampling is carried out after 30 minutes.

Test solution: taking out a proper amount of the dissolved solution, filtering, precisely measuring 5ml of the subsequent filtrate, placing the filtrate into a 25ml measuring flask, diluting to a scale with 0.1mol/L hydrochloric acid solution, and shaking uniformly.

Control solution: and taking a proper amount of riluzole reference substance, precisely weighing, adding 0.1mol/L hydrochloric acid solution for dissolution, and quantitatively diluting to prepare a solution containing about 10 mug per 1 ml.

Assay: taking the sample solution and the reference substance solution, measuring absorbance at 254nm wavelength respectively according to ultraviolet-visible spectrophotometry (generally 0401), and calculating the dissolution amount of each tablet.

Limit: 80% of the indicated amount should be in compliance with the regulations.

Table 3 dissolution rates of examples and comparative examples

4. Related substances

The measurement was performed by high performance liquid chromatography (general rule 0512).

Test solution: taking a proper amount of fine powder of the product, adding a mobile phase to dissolve and dilute the riluzole to prepare a solution containing about 0.5mg of riluzole in each 1ml, filtering, and taking a subsequent filtrate.

Control solution: precisely measuring 1ml of the sample solution, placing in a 100ml measuring flask, diluting to scale with mobile phase, and shaking.

Chromatographic conditions: octadecylsilane chemically bonded silica is used as a filler; methanol-water (70:30) is used as a mobile phase; the detection wavelength is 221nm; the sample volume was 10. Mu.l.

System applicability requirements: the theoretical plate number is not lower than 2000 calculated by Lufeng.

Assay: precisely measuring the sample solution and the control solution, respectively injecting into a liquid chromatograph, and recording the chromatogram till 3 times of the retention time of the main component peak.

Limit: the chromatogram of the sample solution has impurity peaks, the area of single impurity peak is not more than 0.5 times (0.5%) of the main peak area of the control solution, and the sum of the areas of the impurity peaks is not more than the main peak area (1.0%) of the control solution.

( Acceleration test conditions: temperature 40 ℃ ± 2%, relative humidity: 75% ± 5% )

Table 4 examples and comparative examples related to the content of substances

5. Content of

Measured by ultraviolet-visible spectrophotometry (general rule 0401).

Test solution: taking 20 pieces of the product, precisely weighing, grinding, precisely weighing a proper amount of fine powder (about 50mg equivalent to riluzole), placing into a 250ml measuring flask, adding 0.1mol/L hydrochloric acid solution to dissolve riluzole (ultrasound if necessary) and dilute to scale, shaking uniformly, filtering, precisely weighing 5ml of the subsequent filtrate, placing into a 100ml measuring flask, diluting to scale with 0.1mol/L hydrochloric acid solution, shaking uniformly.

Assay: taking the sample solution and the reference substance solution, measuring absorbance at 254nm wavelength, and calculating.

Table 5 results of the riluzole content test in examples and comparative examples

As can be seen from tables 3 and 4, the preparations of this example have low content of the relevant substances, high stability and high content of the active ingredients. Comparative examples the content of the relevant substances was high and the content of the effective components was low after the kinds of the stabilizers were not added and replaced and the ratio of the stabilizers to the microspheres was changed.

6. Time limit of disintegration

The disintegration time was measured according to the disintegration time test method of the four-part rule 0921 in the chinese pharmacopoeia 2020.

Table 6 example and comparative example determination of disintegration time of orally disintegrating tablets

The above experimental data are all carried out under the condition that the tablet or the granule or the quality control meets the standard, and the measurement of the appearance shape, the tablet weight difference, the hardness, the friability, the content uniformity, the appearance shape, the granularity, the loading weight difference, the loading amount and the like of the tablet are all in accordance with the pharmacopoeia specifications, so the experimental data are not listed one by one.

Claims

1. The riluzole microsphere is characterized by comprising riluzole, a carrier material, a coagulant, a cross-linking agent and a buffer, wherein the buffer comprises a buffer A and a buffer B, and the following components in parts by weight are calculated:

45-60 parts by weight of riluzole

60-100 parts by weight of carrier material

10-30 parts by weight of coagulant

5-25 parts by weight of a crosslinking agent

Proper amount of buffer A

5-15 parts by weight of a buffering agent B;

the carrier material is selected from one or more of alginate, chitosan, amino acid, cellulose acetate titanate, ethyl cellulose, methyl cellulose, hypromellose, starch, povidone, lactic acid-glycolic acid, polyamide, chitin and albumin; the coagulant is selected from one of glucose, sodium sulfate, potassium sulfate, ammonium sulfate, potassium thiocyanate, sodium chloride, potassium chloride, ethanol and propanol; the cross-linking agent is one of chloride, sulfate and carbonate; the buffer A is citrate buffer; the buffer B is phosphate buffer.

2. The riluzole microsphere according to claim 1, wherein the coagulant is sodium sulfate; the cross-linking agent is calcium chloride; the carrier material is sodium alginate and starch.

3. The riluzole microsphere according to claim 2, wherein the weight ratio of starch to sodium alginate is 1:1-4.

4. The riluzole microsphere according to claim 2, wherein the weight ratio of starch to sodium alginate is 1:2.

5. The riluzole microsphere according to any one of claims 1-3, wherein the riluzole microsphere comprises the following components in parts by weight:

6. a method of preparing the riluzole microsphere according to claim 1, comprising the steps of:

7. The riluzole microsphere according to claim 1, wherein the riluzole microsphere can be prepared into a preparation with pharmaceutically acceptable auxiliary materials, wherein the preparation comprises but is not limited to orally disintegrating tablets, granules, capsules, pills, powder, chewable tablets, lozenges and suspensions.

8. A formulation according to claim 7, wherein the adjuvant comprises a stabilizer.

9. The formulation of claim 8, wherein the stabilizer is alanine.

10. The formulation of claim 8, wherein the weight ratio of stabilizer to riluzole microspheres is 1:5-30.