CN110585159B

CN110585159B - Tablet containing sirolimus

Info

Publication number: CN110585159B
Application number: CN201910862630.2A
Authority: CN
Inventors: 金冕; 卢良华
Original assignee: Hangzhou Huadong Medicine Group Pharmaceutical Research Institute Co ltd
Current assignee: Hangzhou Huadong Medicine Group Pharmaceutical Research Institute Co ltd
Priority date: 2019-09-12
Filing date: 2019-09-12
Publication date: 2021-11-02
Anticipated expiration: 2039-09-12
Also published as: CN110585159A

Abstract

The invention discloses a tablet containing sirolimus, which comprises an inert tablet core and a coating layer containing sirolimus. Wherein the coating layer comprises the following components: 1 part of sirolimus, 30-50 parts of water-soluble solid dispersion carrier, 1-3 parts of adhesive and 5-15 parts of pore-forming agent; wherein the water-soluble solid dispersion carrier is polyvinylpyrrolidone, the adhesive is hydroxypropyl methylcellulose, and the pore-forming agent is polyethylene glycol. The invention prepares the coating liquid by a solid dispersion technology and coats the coating liquid on the outer layer of the inert tablet core, thereby achieving the purposes of smooth release and stable quality. The sirolimus tablet disclosed by the invention can be prepared by adopting a conventional process, and is suitable for industrial production.

Description

Tablet containing sirolimus

Technical Field

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition containing sirolimus and a preparation method thereof.

Background

Sirolimus, also called rapamycin, is a lipophilic triene nitrogen-containing macrolide immunosuppressant produced by streptomyces hygroscopicus (streptomyces hygroscopicus) separated from soil samples of the Pacific Easler island in 1975, and the sirolimus, also called rapamycin, is soluble in organic solvents such as methanol, ethanol, propanol, chloroform and the like, is very slightly soluble in water and is almost insoluble in ether.

Sirolimus is an immunosuppressant and has anti-lymphocyte proliferation, anti-tumor and anti-fungal effects. The medicine can inhibit activation and proliferation caused by T lymphocyte antigen and cytokine (IL-2, IL-4) stimulation reaction. The action mechanism of the medicine is completely different from other immunosuppressive agents such as tacrolimus, cyclosporine and the like, and the medicine blocks the middle and later periods in the cell cycle process of the G1 phase, inhibits the proliferation of IL-2 dependent and IL-2 independent B lymphocytes, and inhibits the generation of immunoglobulin A, M and G, thereby preventing the activation of an immune system and the conduction of organ rejection reaction signals. The product can bind to FK-binding protein-12 (FKBP-12) in cells, and the complex has effect on calcineurin (calcein) activity. In vivo and in vitro studies prove that the combination of sirolimus and cyclosporine has an immune coordination effect, and the dosage of cyclosporine and corticoid drugs can be reduced by the synergistic effect of sirolimus, so that the toxicity is greatly reduced.

Sirolimus (sirolimus) is used as a third-generation immunosuppressant, is a novel powerful immunosuppressant with low toxicity discovered so far, has the immune effect 100 times stronger than that of cyclosporine and 30 times stronger than that of tacrolimus, but has low oral bioavailability and narrow treatment window due to the fact that the sirolimus belongs to a typical insoluble medicament, and has high incidence rate of adverse reactions such as hypertriglyceridemia, hypercholesterolemia and the like, thereby limiting the wide application of the sirolimus in clinic.

Through technical improvement in the industry for many years, the sirolimus tablet and the formula overcome the technical defect of slow dissolution. At present, a wet granulation method is mostly adopted to prepare sirolimus tablets, but the prepared tablets generally have the technical defects of over-fast dissolution and inconsistent dissolution curves. Such as:

the patent CN200510105774.1 adopts a solid dispersion technology to prepare the sirolimus preparation, but only solves the problem of low in-vitro dissolution rate of the sirolimus, and has the dissolution rate faster than that of an imported sample, so that the effect of stable release cannot be achieved. Because of the narrow therapeutic window of sirolimus, it has also been developed into sustained-release preparations, for example, patent CN200810071842.0 (title of the invention: sirolimus sustained-release preparation and its preparation method) adopts solid dispersion technology to prepare sustained-release preparation containing sirolimus and intermediate, and then adds skeleton material to prepare sustained-release preparation. However, the sirolimus intermediate is prepared by grinding, and the added skeleton material is a slow-release material, so that the process is relatively complex.

In the patent 200710026136.X (the invention name: sirolimus dispersible tablet and the preparation method thereof), the sirolimus dispersible tablet is prepared by adopting a solid dispersion technology. The formula of the invention contains sirolimus, poloxamer F68, microcrystalline cellulose, hydroxypropyl betacyclodextrin, crospovidone, aerosil and magnesium stearate; dissolving sirolimus, poloxamer F68, hydroxypropyl betacyclodextrin and 1/2 micropowder silica gel in absolute ethyl alcohol, and drying at normal temperature under reduced pressure to obtain powder; uniformly mixing microcrystalline cellulose, crospovidone and 1/2 micropowder silica gel, and drying to obtain powder; and then adding magnesium stearate into the powder obtained in the steps 1 and 2, mixing and tabletting to obtain the tablet. Although the preparation process is simple, the dispersible tablet prepared by the method is released too fast, the drug treatment window of sirolimus is narrow, and the toxicity effect is easily caused by the drug concentration in vivo.

Currently marketed sirolimus tablets employ the technique of US 5989591. The preparation method of the sirolimus tablet disclosed by the patent comprises the following steps: sirolimus with the average particle size of below 400nm is adopted, and the ratio of the sirolimus to the sirolimus is 2-6: 1 was dispersed in PLURONIC F68 (poloxamer 188), sucrose was added, povidone was added and mixed until well wetted. The mixture was mixed vigorously to dissolve. Microcrystalline cellulose was added and mixed thoroughly until wet. Water is added, mixed thoroughly, and the mixture is sprayed onto the pharmaceutically inert core in portions and air dried between the portions until the desired tablet strength is formed. In the formulation and the preparation method, it is necessary to control the particle size of sirolimus to 400nm or less, and there is a great difficulty in industry. If the nano particles are to be obtained, the particles need to pass through unconventional crushing equipment, and the particles are easy to agglomerate, so that the particle size detection is difficult. In addition, the coating process is complex, long in time consumption and uncontrollable in quality in terms of industry because multiple times of medicine application and air drying are needed.

Therefore, a sirolimus tablet prescription which can dissolve stably and release slowly and is convenient for industrialization is always searched in the industry.

Disclosure of Invention

The invention aims to provide a safe, stable and controllable sirolimus tablet formula, and the preparation process is simple and efficient, and is suitable for industrial mass production.

The invention discloses a sirolimus tablet, which comprises a pharmaceutically inert/blank tablet core and a coating layer containing sirolimus, wherein the inert/blank tablet core can be collectively called as an inert tablet core and can contain lactose, microcrystalline cellulose and other binders and fillers. Can be prepared or purchased by a conventional method, and only needs to be consistent with no disintegration within 2 hours in the dissolution process. Or can be prepared by adopting the method of the invention.

The coating comprises the following components in parts by mass:

sirolimus 1

Water soluble solid dispersion carrier 30-50

Adhesives 1 to 3

Pore-forming agent 5-15

Wherein the water-soluble solid dispersion carrier is polyvinylpyrrolidone;

wherein the adhesive is hydroxypropyl methylcellulose;

the pore-foaming agent is polyethylene glycol.

Wherein the water-soluble solid dispersion carrier is preferably 40 parts by mass.

Wherein the binder is preferably 1.3 parts by mass.

The pore-foaming agent is preferably 10 parts by mass.

The invention relates to a method for preparing sirolimus tablets according to claim 1, wherein the inert core is coated with the coating solution uniformly.

The invention discloses a preparation method of sirolimus tablets, which is characterized in that coating liquid containing all components of a coating layer is uniformly coated on an inert tablet core.

The coating solution is prepared by the following steps:

uniformly mixing sirolimus and a water-soluble solid dispersion carrier, dissolving the mixture in ethanol,

dissolving the adhesive and the pore-forming agent in water in sequence,

the two solutions were mixed well.

The ethanol may be in various concentrations, such as those commonly used in the formulation art, such as 50%, 70%, 95%, anhydrous ethanol, etc., as long as complete dissolution of sirolimus and the water-soluble solid dispersion carrier is achieved. For the subsequent coating efficiency, a 95% concentration or absolute ethanol is preferred.

The sirolimus tablet disclosed by the invention can be prepared by adopting the following steps:

dissolving the adhesive and the pore-forming agent in water in sequence,

mixing the two solutions uniformly to obtain coating solution,

the prepared coating liquid is uniformly coated on the inert tablet core.

The invention prepares the coating liquid by a solid dispersion technology and coats the coating liquid on the outer layer of the inert tablet core, thereby achieving the technical effect of slow release. Meanwhile, the stability is superior to that of the prior art such as the original imported preparation. The sirolimus tablet provided by the invention can be prepared by adopting a conventional process, and is suitable for industrial production.

Detailed Description

The technical solution and the effects of the present invention will be further described with reference to the following examples. It should be understood that the examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.

Example 1: preparation of inert tablet cores

10 ten thousand prescriptions:

adding in: 10115.6 kg of microcrystalline cellulose

Starch 5.2kg

HPMC_K100MCR 5.2kg

5％HPMC_E510kg of aqueous solution

Adding: magnesium stearate 0.14kg

Preparation: adding adjuvants, mixing, adding the prepared HPMC aqueous solution, stirring, granulating, fluidized bed drying, grading, adding magnesium stearate, and tabletting to obtain 10 ten thousand inert tablet cores with hardness not less than 20 kg.

Example 2

Prescription of 10 ten thousand tablets

Sirolimus 0.1kg

Polyvinylpyrrolidone 4kg

HPMC_K100MCR0.13kg

PEG4000 1.0kg

13.3kg of absolute ethyl alcohol

6.67kg of water

Preparation:

uniformly mixing sirolimus and polyvinylpyrrolidone, and dissolving in absolute ethyl alcohol;

dissolving PEG and HPMC in water in sequence;

mixing the two solutions uniformly;

the inert tablet core prepared as in example 1 was coated with the above coating solution uniformly. Sample 1 was obtained.

Examples 3 to 10

The coating formulations (parts by mass) of examples 3 to 10 were as follows, in which 133 parts of 95% ethanol and 66.7 parts of water were used. The preparation method is the same as that of example 2.

	Sirolimus	Polyvinylpyrrolidone	HPMC_k100mcr	Polyethylene glycol
					Example 3	1	30	1	5
Example 4	1	50	3	15
					Example 5	1	20	1.3	10
Example 6	1	60	1.3	10
					Example 7	1	40	0.8	10
Example 8	1	40	4	10
					Example 9	1	40	1.3	3
Example 10	1	40	1.3	18

Examples 11 to 15

The coating formulations of examples 11 to 15 were as follows, wherein 133 parts of 95% ethanol and 66.7 parts of water were each used. The preparation method is the same as that of example 2.

Example 16

See patent CN200510105774.1 for example 2 preparation.

Prescription: adding in: microcrystalline cellulose 5g

Lactose 5g

Sodium carboxymethyl starch 0.3g

Adhesive: povidone K-300.5 g

Sirolimus 0.1g

80% ethanol solution 10g

Adding: differential silica gel 0.15g

Magnesium stearate 0.15g

Making into 100 pieces

The preparation method comprises the following steps: sieving microcrystalline cellulose, lactose and sodium carboxymethyl starch with 80 mesh sieve, respectively weighing microcrystalline cellulose 5g, lactose 5g and sodium carboxymethyl starch 0.3g, and mixing. The sirolimus and povidone-K30 are dissolved in ethanol-water (8:2) to prepare a solution as a binder, the above filler mixture is added to prepare a soft material, and the soft material is sieved by a 18-mesh sieve to prepare wet granules. Adding a lubricant and a glidant, and tabletting to obtain the sirolimus tablet.

Example 17

Reference is made to patent 200710026136.X, example 1 preparation.

The preparation method comprises the following steps:

1. adding the sirolimus, the poloxamer F68, the hydroxypropyl beta cyclodextrin and half of the prescription amount of superfine silica powder into absolute ethyl alcohol for dissolving, then spreading the mixture in a tray, reducing pressure at normal temperature, wherein the pressure is as follows: 0.08MPa, drying into powder, wherein the drying time is as follows: sieving the mixture for 8 hours by using a 80-mesh sieve for later use;

2. and then placing the microcrystalline cellulose, the crospovidone and half of the remaining prescription amount of the micro-powder silica gel into a mixer to be uniformly mixed at a rotating speed: 10r/min, spreading in a tray, drying in an oven to obtain powder, wherein the drying temperature is as follows: and at 85 ℃, the drying time is as follows: 5 hours, standby;

3. and (3) combining the powders obtained in the steps (1) and (2), adding the powders into a mixer, mixing, adding magnesium stearate, fully mixing uniformly, adding the mixture into a hopper of a tabletting machine, and tabletting (by a conventional method).

EXAMPLE 18 dissolution test

The experimental method comprises the following steps:

and (4) carrying out dissolution and lightproof operation. Taking a sample, taking 500ml of 0.4% sodium dodecyl sulfate solution as a dissolution medium according to a dissolution determination method (first method of appendix XC of the second part of the 2010 edition of Chinese pharmacopoeia), operating according to the method at the rotating speed of 120 revolutions per minute, taking 10ml of solution after 60 minutes, filtering, and taking a subsequent filtrate as a sample solution; and precisely weighing a proper amount of sirolimus reference substance, placing the sirolimus reference substance into a 50ml measuring flask, adding methanol for dissolving and quantitatively diluting to prepare a solution containing 0.2mg of sirolimus in each 1ml, precisely weighing a proper amount of sirolimus, placing the solution into a 100ml measuring flask, and quantitatively diluting the solution with a dissolution medium to prepare a solution containing 2 mu g of sirolimus in each 1ml as a reference substance solution. Performing high performance liquid chromatography (appendix V D of second part of 2010 edition in Chinese pharmacopoeia) with octadecylsilane chemically bonded silica as filler; methanol-acetonitrile-water (60: 20: 20) is used as a mobile phase, the column temperature is 45 ℃, and the detection wavelength is 277 nm. Precisely measuring 20 mul of each of the test solution and the reference solution, respectively injecting into a liquid chromatograph, recording the chromatogram, and calculating the dissolution amount of each particle according to the sum of the main peak area and the isomer peak area by an external standard method. The dissolution curve and the F2 value of the tablets with import tablets (Huwler, USA, batch No. S84786) are shown in the table below.

EXAMPLE 19 substance testing

The related substances are protected from light. Taking a proper amount of sirolimus fine powder (about 5mg of sirolimus), putting the sirolimus fine powder into a 10ml measuring flask, adding acetonitrile-water-glacial acetic acid (80:20:0.5) to dissolve and dilute the sirolimus fine powder to a scale, shaking up, filtering, and taking a subsequent filtrate as a sample solution; an appropriate amount was precisely measured and quantitatively diluted with the above solvent to prepare a solution containing 25. mu.g of the solvent per 1ml, which was used as a control solution. According to the chromatographic conditions under the content determination item, taking 10 mu l of the reference solution, injecting the reference solution into a liquid chromatograph, and adjusting the sensitivity of the instrument to enable the peak height of the main component chromatographic peak to be about 10-15% of the full-scale range; then, 10. mu.l of each of the test solution and the control solution was measured precisely and injected into a liquid chromatograph, and the retention time of the chromatogram to the main component peak was recorded to 2.5 times. If an impurity peak exists in a chromatogram of the test solution, the peak area of the rapamycin (relative retention time to the sirolimus main peak is about 0.32) should not be larger than 2/5 (2.0%) of the main peak area of the control solution; the sum of the peak areas of the individual impurities, excluding the isomer peak, must not be greater than the main peak area (5.0%) of the control solution.

The samples of examples 2 and 18 were placed in a suitable clean container with an opening and left at 40 ℃ for 10 days, and the substances involved were measured as shown in the following table. The test results show that the high temperature stability of sample 1 is significantly superior to that of the inlet sheet (U.S. Huwler production, lot # S84786).

The dissolution curves of examples 2 to 17 were measured, respectively, as shown in the attached table. The data show that the dissolution curves of examples 5-17 in 0.4% SDS aqueous solution of standard medium are different from the inlet tablet in different degrees. The dissolution profiles of examples 2-4 were consistent with the inlet tablets, with example 2 having the highest value of F2 (i.e., the most consistent with the dissolution profile of the inlet tablets), thereby indicating that the patent samples released as smoothly as the inlet tablets. And sample stability example 2 is superior to the inlet tab. Therefore, the stability of the sample is better solved, and the dissolution rate is ensured to be consistent with that of the imported tablets, so that the method is safer and more effective.

Claims

1. A sirolimus-containing tablet consisting of an inert core and a sirolimus-containing coating layer, wherein the coating layer comprises the following components in parts by mass:

sirolimus 1

Water soluble solid dispersion carrier 30-50

Adhesives 1 to 3

Pore-forming agent 5-15

Wherein the water-soluble solid dispersion carrier is polyvinylpyrrolidone;

wherein the adhesive is hydroxypropyl methylcellulose K100 mcr;

the pore-foaming agent is polyethylene glycol 4000.

2. The sirolimus-containing tablet of claim 1, wherein the water-soluble solid dispersion carrier is 40 parts by mass.

3. The sirolimus-containing tablet of claim 1, wherein the binder is 1.3 by mass.

4. The sirolimus-containing tablet of claim 1, wherein the pore-forming agent is 10 by mass.

5. A process for the preparation of a sirolimus-containing tablet as set forth in claim 1, characterized in that a coating solution containing a coating layer component is uniformly coated on the inert core.

6. The method according to claim 5, wherein the coating solution is prepared by the steps of:

dissolving the adhesive and the pore-forming agent in water in sequence,

the two solutions were mixed well.

7. The method according to claim 6, wherein the ethanol is 95% strength ethanol or absolute ethanol.