CN110037992B

CN110037992B - Stable fidaxomicin composition

Info

Publication number: CN110037992B
Application number: CN201910454081.5A
Authority: CN
Inventors: 谢羽能; 白海波
Original assignee: Hangzhou Huadong Medicine Group Biopharmaceutical Co ltd
Current assignee: Hangzhou Huadong Medicine Group Biopharmaceutical Co ltd
Priority date: 2019-05-28
Filing date: 2019-05-28
Publication date: 2021-05-28
Anticipated expiration: 2039-05-28
Also published as: CN110037992A

Abstract

The application discloses a pharmaceutical composition containing fidaxomicin and a preparation method thereof. According to the fidaxomicin-containing composition provided by the invention, the water adding amount in the wet granulation process, the stirring speed in granulation and the wet granulation time are improved, so that the prepared fidaxomicin-containing composition has good stability, the related substances are less increased, the medicine quality standard is met, the requirement on temperature in the storage and transportation link can be reduced, and the dissolution is stable even under the condition that an antioxidant is not added.

Description

Stable fidaxomicin composition

Technical Field

The invention relates to a pharmaceutical composition, in particular to a stable pharmaceutical composition containing fidaxomicin and a preparation method thereof.

Background

Fidaxomicin (trade name difficid) is the first of a new class of oral narrow spectrum macrocyclic antibiotics developed by Optimer, is a macrolide antibiotic with an 18-membered ring structure, belongs to class B tiacumicins, and has a novel action mechanism. Fidaxomicin was approved by the FDA in the united states for marketing in 5 months of 2011 and was used to treat diarrhea associated with Clostridium difficile (CDAD). This was the first drug approved by the FDA for the treatment of CDAD in the last 30 years. The european union is approved for marketing in 2011 in 12 months.

The structural formula is as follows:

the polyene macrolide antibiotics have a plurality of conjugated olefinic bonds and hydroxyl groups in the structure, the existence of the active groups enables fidaxomicin to easily generate oxidation reaction, particularly the oxidation reaction is enhanced along with the increase of temperature and humidity, and in order to prevent the autoxidation of the medicine, one or more antioxidants are generally added in the preparation process. For example, in the stabilized tiacumicin composition (application No. 2008800078761), in order to solve the stability of fidaxomicin, 0.001-50% of antioxidant, specifically one or both of BHA and BHT, is added to the pharmaceutical composition to achieve a good antioxidant effect. Thereby achieving the technical effect that the related substances are lower than the composition without the antioxidant. However, in the preparation, any auxiliary material needs to be subjected to quality control and detection; one more auxiliary material is added, so that one more quality risk exists.

Fidaxomicin is a BCS (biopharmaceutical Classification System) class IV compound with low solubility and low permeability. Therefore, in clinical use, in order to ensure better bioavailability, better dissolution rate must be ensured. In the patent 'a stable fidaxomicin pharmaceutical composition' (application number 201410628815.4), the problem of low dissolution rate is solved by adjusting the prescription; a fidaxomicin solid dispersion and a preparation method thereof (application No. 201310494941.0) solve the problem of low solubility by dissolving or dispersing fidaxomicin in an enteric carrier material and adopting a hot-melt extrusion method; the tiacumicin compound-containing composition (application No. 201480015374.9) is prepared into granules by adopting excipients such as xanthan gum, carrageenan, sodium alginate, guar gum and the like, and is preferably prepared into aqueous suspension to meet the requirement of dissolution rate. In conclusion, in the field of preparation, different types of auxiliary materials, combinations of the amounts of the auxiliary materials and the preparation method can produce different dissolution effects, and meanwhile, preparations with different stabilities can also be produced for moisture-heat sensitive raw materials, which is difficult to be inferred by the professional.

The impurity F is the most important degradation impurity of fidaxomicin raw material sensitive to humidity and heat, can generate large change along with the change of temperature and humidity, is one of evaluation indexes for stability investigation, and needs to be strictly controlled to meet the quality standard of medicines, thereby having higher requirements on storage and transportation.

For the pharmaceutical products, in addition to controlling the process impurities, the degradation impurities need to be controlled for the pharmaceutical products due to the drug efficacy and the safety of the drugs. When a product sold in the original research company is detected, the process impurities, such as A impurities, are controlled strictly, but the degradation impurities, such as F impurities, are controlled loosely, so that the phenomenon that the F impurities of the medicine sold in the market are high exists.

Therefore, there is a great need in the art for a pharmaceutical composition and a preparation method thereof, which can achieve stable quality and achieve better dissolution rate even without containing an antioxidant.

Disclosure of Invention

The invention discloses a fidaxomicin composition which has good dissolution rate, can not contain antioxidant and is stable, and the composition is obtained by optimizing a preparation process.

The invention provides a method for preparing a pharmaceutical composition containing fidaxomicin, which comprises the following steps of preparing fidaxomicin-containing granules by wet granulation: premixing fidaxomicin, microcrystalline cellulose, pregelatinized starch, carboxymethyl starch sodium and hydroxypropyl cellulose, adding ethanol, adding water, and granulating; wherein the added water accounts for 42 to 52 percent of all the materials in terms of mass volume ratio; the granules are then compressed into a pharmaceutical composition.

Wherein, the stirring speed during granulation is 60-115 m/min; preferably 88 m/min. The stirring rate during granulation refers to the stirring rate until the end of granulation. The stirring rate during premixing may be the same as or different from the granulation stirring rate.

Wherein the granulation time is 3-6 min; preferably 4.5 min.

Wherein, the water addition amount is preferably 47 percent of all materials in terms of mass volume ratio.

The invention also discloses a fidaxomicin-containing composition, which is prepared by the following method: preparing fidaxomicin-containing granules by wet granulation, wherein the wet granulation comprises the following steps: premixing fidaxomicin, microcrystalline cellulose, pregelatinized starch, carboxymethyl starch sodium and hydroxypropyl cellulose, adding ethanol, adding water, and granulating; wherein the added water accounts for 42 to 52 percent of all the materials, preferably 47 percent by mass volume ratio; the granules are then compressed into a pharmaceutical composition. Wherein, the stirring speed during granulation is 60-115 m/min; preferably 88 m/min. The stirring rate during granulation refers to the stirring rate until the end of granulation. The stirring rate during premixing may be the same as or different from the granulation stirring rate. Wherein the granulation time is 3-6 min; preferably 4.5 min.

The fidaxomicin-containing composition disclosed by the invention is a solid pharmaceutical composition for oral administration, and can be prepared into tablets, capsules, granules and other dosage forms suitable for oral administration by using a conventional process, and preferably is in the form of tablets.

According to the preparation method provided by the invention, the water adding amount in the wet granulation process, the stirring speed in granulation and the wet granulation time are improved, so that the prepared fidaxomicin-containing composition has less related substance increase, meets the medicine quality standard, can reduce the requirement on temperature in the storage and transportation link, and is stable in dissolution even under the condition of not adding an antioxidant.

Detailed Description

The equipment adopted by the invention is as follows:

granulator Bosch Mycromix, Pilotmix 50T granulation line wet granulator;

fluidized bed Solidlab, Pilotlab L granulation line fluidized bed

Moisture meter Sartorius MH100, MB35 rapid moisture meter;

whole-grain QUADRO COMIL U5-0437R, HLS-100 hopper mixer;

rotary tablet press ZPS8, BB4 tablet press.

The commercial samples were:

the manufacturer: optimer Pharmaceuticals, inc. trade name: DIICID; product batch number: HTZY.

Example 1

Prescription:

the preparation method comprises the following steps:

1. weighing raw materials, microcrystalline cellulose, pregelatinized starch, carboxymethyl starch sodium and hydroxypropyl cellulose, pouring into a granulator Bosch Mycromix, premixing for 3min, and stirring at a speed of 60 m/min;

2. after the premixing is finished, adding ethanol, continuously stirring, slowly adding pure water, continuously stirring, wherein the stirring speed is 115m/min, and the granulating time is 6 min. After the completion of granulation, the wet granules were granulated, and the screen was provided with 4 × 4mm square holes at a speed of 1000 rpm.

3. Fluidized bed Solidlab is used for drying, the air inlet temperature is 60 ℃, and the water content is 1.0-3.0%.

4. Whole grain QUADRO COMIL U5-0437R, screen mesh diameter phi 1.5mm, rotation speed 1000 rpm.

5. Adding the added carboxymethyl starch sodium and magnesium stearate according to the prescription amount, mixing uniformly, and tabletting by a rotary tablet machine ZPS 8.

Examples 2 to 7

Examples 2 to 7 were the same as example 1 except that the amount of water added, the stirring speed for granulation, and the granulation time were as shown in the table.

Examples	Water content is added%	Amount of added water g	Linear velocity (m/min)	Granulation time (min)
					2	52％	270	61	6
3	42％	220	61	3
					4	52％	270	115	3
5	42％	220	115	6
					6	52％	270	61	3
7	47％	245	88	4.5

Example 8

Prescription:

the preparation method comprises the following steps:

1. weighing raw materials, microcrystalline cellulose, pregelatinized starch, carboxymethyl starch sodium and hydroxypropyl cellulose, pouring into a Pilotmix 50T granulating line wet granulator of a granulator, premixing for 3min, and stirring at 88 m/min;

2. after the premixing is finished, adding ethanol, continuously stirring, slowly adding pure water, and continuously stirring, wherein the stirring speed is 88m/min, and the granulating time is 4.5 min. After the completion of granulation, the wet granules were granulated, and the screen was provided with 4 × 4mm square holes at a speed of 1000 rpm.

3. The Pilotlab L granulation line is dried by a fluidized bed, the air inlet temperature is 60 ℃, and the moisture content is measured by an MB35 rapid moisture content measuring instrument to be 1.0-3.0%.

4. The aperture of the screen mesh is 1.5mm, and the rotating speed is 1000 rpm.

5. Adding the added carboxymethyl starch sodium and magnesium stearate according to the prescription amount, mixing the mixture by a HLS-100 hopper mixer, and tabletting by a BB4 tabletting machine.

Example 9

Referring to example 7, a sample was prepared by adding 0.045 g of antioxidant Butylated Hydroxytoluene (BHT) to the formulation in the same manner as in example 7.

Example 10: results of dissolution test

The 9 compositions prepared above were subjected to a 10-minute dissolution test in ph6.8+ 0.1% sodium lauryl sulfate (sds). The detection method comprises the following steps: 900ml of ph6.8+ 0.1% sds solution, 37 ℃,50rpm paddle method, 230nm, 0.5mm probe. Equipment: FODT-601 fiber optic real-time drug dissolution rate tester. The dissolution results are shown below:

the results above show that the formulations are very similar to the commercial samples except for example 1 in ph6.8+ 0.1% sds solution, but the 9 combinations f2 are greater than 50 and dissolve consistently with the commercial samples.

Example 11: stability test

The samples prepared in examples 1 to 9 were sealed in bottles, placed in 40 ℃ RH 75% conditions, sampled at 0, 1, 2, 3, and 6 months, and tested for related substances by HPLC.

The detection device comprises: an Agilent 1260 liquid chromatograph is adopted,

the detection method comprises the following steps:

chromatographic conditions are as follows:

a chromatographic column: agilent poroshell 120 EC-C₁₈ 100×4.6mm 2.7μm

Column temperature: 15 deg.C

Mobile phase: 0.05M potassium dihydrogen phosphate solution (pH adjusted to 2.5. + -. 0.1 with phosphoric acid) -acetonitrile (50:50)

Flow rate: 0.5ml/min

DAD detector (detection wavelength 230nm)

Temperature of a sample injection tray: 5 deg.C

Sample introduction volume: 10 μ l

Diluting the solvent: citrate buffer pH4 (1.9 g of anhydrous citric acid dissolved in about 1000ml of HPLC grade water adjusted to 4.0. + -. 0.1 with 10N NaOH) -acetonitrile (200:300)

The specific test operation is as follows: taking 10 samples, precisely weighing, grinding, precisely weighing an appropriate amount, dissolving with a diluent solvent, quantitatively diluting to obtain a solution containing about 0.25mg per 1ml, filtering, and taking the subsequent filtrate as a sample solution; an appropriate amount of the above solution was precisely measured and diluted quantitatively with a diluting solvent to prepare a solution containing about 2.5. mu.g of the solution per 1ml as a control solution. Injecting 10 mul of the contrast solution into a liquid chromatograph, adjusting the detection sensitivity to ensure that the peak height of the main component chromatographic peak is about 20-30% of the full scale, precisely measuring 10 mul of each of the test solution and the contrast solution, and recording the chromatogram until the retention time of the main peak is 3 times. Deducting the auxiliary material peak, recording the main peak area in the control solution as At and the peak area of each single impurity as Ai, calculating the content of the impurity according to the ratio of the peak area of the single impurity to the main peak area of the control solution, and calculating the total amount of the impurity according to the ratio of the sum of the peak areas of the impurities to the main peak area of the control solution.

Calculating the formula: amount of individual impurities Ai/At (%)

Total impurities ═ Sigma Ai/At (%)

RRT: relative retention time

The prescription of the invention prepares the obtained pharmaceutical composition:

1. dissolution was comparable to commercial samples:

2. the impurity F at 0, the impurity F at 6 months and the total impurity at 0 are all lower than those of the commercial product in the pharmaceutical composition prepared by the preparation process;

3. after 6 months accelerated stability test, the increase amount of impurities F and total impurities of the medicine composition prepared by the preparation process, especially the sample prepared by the optimized process is equivalent to that of a sample sold in the market;

4. by using the preparation process of the invention, a small amount of antioxidant is added in the prescription, and after 6 months of accelerated stability test, the growth amount of the impurity F and the total impurities is obviously improved compared with the commercial samples.

Thus, the preparation process of the present invention provides a fidaxomicin formulation with good stability prepared without antioxidant.

Claims

1. A process for preparing a pharmaceutical composition comprising fidaxomicin by wet granulation to prepare a fidaxomicin-containing granulate, wherein the wet granulation comprises the steps of: premixing fidaxomicin, microcrystalline cellulose, pregelatinized starch, carboxymethyl starch sodium and hydroxypropyl cellulose, adding ethanol, adding water, and granulating; wherein the added water accounts for 47 percent of all materials in terms of mass volume ratio; the granules were then compressed into a pharmaceutical composition with a stirring rate of 88m/min and a granulation time of 4.5 min.

2. A fidaxomicin-containing composition prepared by the process of claim 1.

3. The fidaxomicin-containing composition according to claim 2, which is a solid pharmaceutical composition for oral administration.

4. The fidaxomicin-containing composition according to claim 2, which is in the form of a tablet.