CN113876735A

CN113876735A - Riluzole microsphere preparation and preparation method thereof

Info

Publication number: CN113876735A
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: 2022-01-04
Anticipated expiration: 2041-10-20
Also published as: CN113876735B

Abstract

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

Description

Riluzole microsphere preparation and preparation method thereof

Technical Field

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

Background

Riluzole, chemically known as 2-amino-6-trifluoromethoxybenzothiazole, is useful for prolonging the life of patients with Amyotrophic Lateral Sclerosis (ALS) or for prolonging their time to develop to the point where mechanical ventilatory support is required. Clinical trials have demonstrated that riluzole can prolong 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 buffering agent, wherein the riluzole sustained-release microspheres are prepared by dissolving riluzole in an ethyl cellulose aqueous dispersion and performing spray drying, and the solid content ratio of riluzole to the ethyl cellulose aqueous dispersion is 1:1-1: 3. Microspheres are used as intermediate carriers of medicines and are often required to be further processed to prepare preparations, so that the quality evaluation of the microspheres is necessary and is also a requirement in pharmacopoeia, such as drug loading rate, encapsulation rate and the like, while the quality evaluation of microsphere intermediates is not carried out in the patent, and whether the quality is qualified or not is unknown. Amyotrophic lateral sclerosis is mainly manifested by muscular atrophy, weakness, difficulty in speaking and swallowing, so the oral suspension is difficult to take by patients with serious amyotrophic lateral sclerosis.

Chinese patent CN 104606683A discloses an oral cavity disintegrating preparation, which comprises main riluzole, collagen peptide and sugar alcohol as auxiliary materials, wherein the collagen peptide and the sugar alcohol mainly account for 3% -20% of the total weight, the collagen peptide accounts for 2% -18% of the total weight, and the sugar alcohol accounts for 15% -80% of the total weight.

Chinese patent CN 111821289B discloses riluzole orally disintegrating tablets and a preparation method thereof, and the riluzole orally disintegrating tablets are prepared from riluzole, sodium bicarbonate, a filling agent, a disintegrating agent, a lubricant and a flavoring agent. However, the patent does not detect the stability of the orally disintegrating tablet with respect to the substance and the like, and the safety of the administration of the orally disintegrating tablet cannot be ensured.

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

Disclosure of Invention

The invention overcomes the defects of the prior art, and provides a riluzole microsphere intermediate and a preparation prepared from the riluzole microsphere intermediate.

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

The components are preferably as follows by weight:

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

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

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

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

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

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

The preparation includes but is not limited to common tablets, orally disintegrating tablets, granules, capsules, pills, powder, chewable tablets, buccal tablets and suspensions.

Further, pharmaceutically acceptable auxiliary materials contained in the preparation can comprise a stabilizer, a filler, a lubricant, a disintegrant and a binder.

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, superfine silica gel powder, magnesium stearate, polyethylene glycol, stearic acid, boric acid and dodecyl sulfate; the disintegrating agent is selected from one or more of dry starch, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, sodium alginate and sodium bicarbonate; the stabilizer is one of amino acids, preferably 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 microspheres of luxol.

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

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

preferably, the first and second liquid crystal materials are,

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

(1) by optimizing the drug-loaded material and the corresponding auxiliary materials, the encapsulation efficiency and the drug-loaded amount of the riluzole microspheres are improved, the problems of loss and deterioration of active ingredients of riluzole are solved, the stability of the drug is improved, and the dissolution rate of the drug is improved;

(2) when the riluzole microsphere intermediate is prepared into a preparation, the stabilizer and the proportion of the stabilizer to 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 types and the proportion of the auxiliary materials are optimized, the orally disintegrating tablet is prepared, the disintegration time limit is shortened, and the problem that other dosage forms are difficult to take medicines for patients with amyotrophic lateral sclerosis is solved.

Detailed Description

In order to make the purpose and technical solution of the present invention more clear, the present invention is further described with reference to the following examples, but the scope of the present invention is not limited to these examples, and the examples are only used for explaining the present invention. It will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true scope of the invention.

Example 1: riluzole microspheres

Preparation of riluzole microspheres:

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

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

Example 2: riluzole microspheres

Preparation of riluzole microspheres:

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

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

Example 3: riluzole microspheres

Preparation of riluzole microspheres:

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

(3) and (3) curing: adding a cross-linking agent and a buffer B (0.5mol/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 crushing mannitol, superfine silica gel powder, low-substituted hydroxypropyl cellulose and alanine according to the prescription amount, and sieving;

(2) mixing; putting the screened mannitol, low-substituted hydroxypropyl cellulose, alanine and riluzole microspheres in the step (1) into a mixer, mixing for 5min, adding superfine silica gel powder, and continuously mixing for 10 min;

(3) granulating, drying, and tabletting.

Example 5: normal sheet (1000 sheet)

The preparation method comprises the following steps:

(1) crushing and sieving: respectively crushing and sieving the microcrystalline cellulose, the talcum powder, the starch and the alanine according to the prescription amount;

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

(3) granulating, drying, and tabletting.

Example 6: granule (1000 tablets)

The preparation method comprises the following steps:

pre-mixing riluzole microspheres, and pouring the pulverized 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 riluzole microsphere.

Example 7: orally disintegrating tablet (1000 tablets)

The preparation method comprises the following steps:

(1) crushing and sieving: respectively crushing and sieving the microcrystalline cellulose, the talcum powder, the crospovidone and the alanine according to the prescription amount;

(2) mixing; placing the microcrystalline cellulose, the crospovidone, the alanine and the riluzole microspheres sieved in the step (1) into a mixing machine to be mixed for 5min, adding the talcum powder and continuously mixing for 10 min;

(3) granulating, drying, and tabletting.

Example 8: orally disintegrating tablet (1000 tablets)

The preparation method comprises the following steps:

(1) crushing and sieving: respectively crushing the starch, the magnesium stearate, the sodium alginate and the alanine according to the prescription amount, and sieving;

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

(3) granulating, drying, and tabletting.

Comparative example 1 riluzole microspheres

Preparation of riluzole microspheres:

Comparative example 2 riluzole microspheres

Preparation of riluzole microspheres:

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

Comparative example 3 orally disintegrating tablet

The preparation method comprises the following steps:

(1) crushing and sieving: respectively crushing mannitol, superfine silica gel powder and low-substituted hydroxypropyl cellulose according to the prescription amount, and sieving;

(2) mixing; putting the screened mannitol, low-substituted hydroxypropyl cellulose and riluzole microspheres in the step (1) into a mixer for mixing for 5min, adding the superfine silica gel powder and continuously mixing for 10 min;

(3) granulating, drying, and tabletting.

Comparative example 4 orally disintegrating tablet

The preparation method comprises the following steps:

(1) crushing and sieving: respectively crushing mannitol, superfine silica gel powder, low-substituted hydroxypropyl cellulose and poloxamer according to the prescription amount, and sieving;

(2) mixing; putting the screened mannitol, low-substituted hydroxypropyl cellulose, poloxamer and riluzole microspheres in the step (1) into a mixer, mixing for 5min, adding superfine silica gel powder, and continuously mixing for 10 min;

(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 examples

1. Drug loading

The drug loading rate refers to the mass percentage of the drugs contained in the microcapsules and the microspheres.

The drug loading was calculated as follows:

the drug loading rate is the amount of the drug contained in the microcapsule or the microsphere/the total amount of the microcapsule or the microsphere is multiplied by 100 percent

Table 1 drug loading of riluzole microspheres 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 in the theoretical dosage, and is an important index for considering the quality of the drug microencapsulation process.

The envelope rate is calculated as follows:

encapsulation rate ═ amount of drug encapsulated in system/total amount of drug encapsulated and unencapsulated in system x 100%

1-unencapsulated dose in liquid medium/total dose encapsulated and unencapsulated in the system x 100%

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

TABLE 2 encapsulation efficiency of riluzole microspheres 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 determination results of the drug loading and encapsulation efficiency of the microspheres shown in tables 1 and 2, the types and the collocation of the carrier material and the curing agent, and the proportion of the drug loading material and the drug have great influence on the drug loading and the encapsulation efficiency of the microspheres.

3. Rate of drug release

Measured by dissolution and release assay (second method of general rule 0931).

Dissolution conditions: 900ml of 0.1mol/L hydrochloric acid solution is used as a dissolution medium, the rotating speed is 50 revolutions per minute, and samples are taken after 30 minutes according to the method.

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

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

The determination method comprises the following steps: taking the test solution and the reference solution, respectively measuring absorbance at 254nm wavelength by ultraviolet-visible spectrophotometry (general rule 0401), and calculating the elution amount of each tablet.

Limitation: 80% of the indicated amounts should be in accordance with the regulations.

Table 3 dissolution of examples and comparative examples

4. Related substances

Measuring by high performance liquid chromatography (general rule 0512).

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

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

Chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filling agent; methanol-water (70:30) is used as a mobile phase; the detection wavelength is 221 nm; the injection volume was 10. mu.l.

System applicability requirements: the number of theoretical plates is not less than 2000 calculated according to the riluzole peak.

The determination method comprises the following steps: precisely measuring the test solution and the reference solution, respectively injecting into a liquid chromatograph, and recording the chromatogram until the retention time of the main component peak is 3 times.

Limitation: if an impurity peak exists in the chromatogram of the test solution, the area of a single impurity peak is not more than 0.5 times (0.5%) of the area of a main peak of the control solution, and the sum of the areas of the impurity peaks is not more than 1.0% of the area of the main peak of the control solution.

(accelerated test conditions: temperature 40 ℃ C. + -. 2%, relative humidity: 75% + -. 5%)

TABLE 4 examples and comparative examples concerning the content of substances

5. Content (wt.)

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

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

The determination method comprises the following steps: taking the test solution and the reference solution, respectively measuring absorbance at 254nm wavelength, and calculating.

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

As can be seen from tables 3 and 4, the preparation of this example has low content of related substances, high stability, and high content of active ingredients. In the comparative example, after the types of the stabilizers are not added or replaced and the proportion of the stabilizers to the microspheres is changed, the content of related substances is high, and the content of effective components is low.

6. Disintegration time limit

The disintegration time is measured according to 0921 disintegration time examination method of the four-part general rules of 2020 edition of Chinese pharmacopoeia.

TABLE 6 determination of disintegration time of orally disintegrating tablets of examples and comparative examples

The above experimental data are all performed in the case where the tablets or granules or quality control meets the standards, and the above examples are all in accordance with the pharmacopoeia regulations with respect to the measurement of the external shape, the difference in tablet weight, the hardness, the friability, the content uniformity of the tablets, and the external shape, the particle size, the difference in weight, the loading amount, etc. of the granules, and therefore, 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 buffering agent, wherein the buffering agent comprises a buffering agent A and a buffering agent B, and the components in parts by weight are as follows:

2. the riluzole microspheres of claim 1, wherein the carrier material is selected from one or more of alginate, chitosan, amino acids, cellulose acetate titanate, ethylcellulose, methylcellulose, hypromellose, starch, povidone, lactic-glycolic acid, polyamide, chitin, 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 a citrate buffer; the buffer B is phosphate buffer.

3. The riluzole microsphere of claim 2, wherein the coagulant is sodium sulfate; the coagulant is chloride salt, preferably calcium chloride; the carrier material is sodium alginate and starch.

4. Riluzole microspheres according to claim 3, characterized in that the weight ratio of starch to sodium alginate is 1:1-4, preferably 1: 2.

5. The riluzole microsphere according to any one of claims 1 to 4, wherein the components are calculated by weight:

6. a process for preparing riluzole microspheres of claim 1 comprising the steps of:

7. The riluzole microspheres of claim 1, wherein the riluzole microspheres can be formulated with pharmaceutically acceptable excipients, and the formulations include, but are not limited to, plain tablets, orally disintegrating tablets, granules, capsules, pills, powders, chewable tablets, buccal tablets, and suspensions.

8. The formulation of claim 7, wherein the excipient comprises a stabilizer.

9. Formulation according to claim 8, characterized in that the stabilizer is one of the amino acids, preferably alanine.

10. The formulation according to claim 8 or 9, wherein the weight ratio of the stabilizer to the riluzole microspheres is 1: 5-30.