CN115607520A

CN115607520A - Stable oxycodone hydrochloride tablet and preparation method thereof

Info

Publication number: CN115607520A
Application number: CN202110784588.4A
Authority: CN
Inventors: 谭成芳; 杨玉萍; 梁佳; 魏弟超; 王敏; 吕金良; 熊俊; 李莉娥; 田峦鸢
Original assignee: Yichang Humanwell Pharmaceutical Co Ltd
Current assignee: Yichang Humanwell Pharmaceutical Co Ltd
Priority date: 2021-07-12
Filing date: 2021-07-12
Publication date: 2023-01-17

Abstract

The invention discloses a stable oxycodone hydrochloride tablet, which comprises 10 parts by weight of oxycodone hydrochloride, 5-25 parts by weight of poloxamer, 70-160 parts by weight of slow release materials, 20-80 parts by weight of alpha-lactose and cellulose accessories, 0.5-5 parts by weight of plasticizer and 1-5 parts by weight of lubricant, and optionally, a coating material. The invention improves the instability problem of the composition containing oxycodone hydrochloride in the production process and the storage process, improves the product quality, prolongs the effective period of the product, and improves the safety and the stability of the composition.

Description

Stable oxycodone hydrochloride tablet and preparation method thereof

Technical Field

The invention belongs to the field of pharmaceutical preparations, and relates to a stable oxycodone hydrochloride tablet and a preparation method thereof.

Background

According to the statistics of the Ministry of health, about 450 ten thousand cancer patients exist in China at present, about 180 thousand newly diagnosed cancer patients die of more than 140 ten thousand cancer patients each year, and about 80% of cancer patients have cancer pain at the late stage, wherein 65% -80% of the pain is moderate and severe pain. It can be said that cancer pain is one of the main causes of pain in patients with advanced cancer, and some patients have treatment interruption due to intolerable cancer pain. Cancer pain seriously affects the quality of life of cancer patients, so analgesic treatment for cancer pain is particularly important for patients with advanced cancer.

Oxycodone hydrochloride is an opioid potent analgesic, is a pure opioid receptor agonist, has the main therapeutic effect of analgesia, and can be used for relieving continuous moderate to severe pain. Oxycodone hydrochloride is widely used clinically, and due to the structural particularity of the oxycodone hydrochloride, the hydroxyl at the 3-position of morphine is replaced by methyl, so that the lipophilicity of the medicine is increased, the transmembrane effect and the capability of penetrating through a blood brain barrier of the oxycodone are further improved, and the bioavailability of the oxycodone hydrochloride is greatly improved and is about 3-4 times that of morphine.

In 1995, oxycodone hydrochloride sustained release tablets developed by general pharmaceutical companies (Purdue Pharma) were marketed as a persistent anesthetic that can help patients to relieve moderate and severe pain, and at that time, it was known as a drug having medical breakthrough. In 2004, otashodin was introduced by the menadipama pharmaceutical company (mundpharma) and approved for marketing at home, with indications for the relief of persistent moderate to severe pain. The olastrodine is prepared by a wet granulation method, and related substances obviously grow in the storage process, so that the quality of the tablet is unstable.

At present, no oxycodone hydrochloride tablet capable of improving the instability problem caused by obvious growth of related substances in the production process and the storage process of a preparation is provided in the prior art at home and abroad.

Disclosure of Invention

The invention aims to provide a stable oxycodone hydrochloride tablet, which solves the problem of instability caused by obvious increase of related substances in the preparation production process and the storage process in the prior art, improves the preparation stability, improves the product quality, prolongs the product validity period and reduces the clinical medication risk.

The inventor of the invention discovers through a large amount of stability experimental researches that the oxycodone hydrochloride tablet adopts a wet granulation process, if auxiliary materials (such as povidone) containing carbonyl in the structure exist in the prescription, the auxiliary materials easily react with raw materials, so that the raw materials are degraded, related substances exceed the specified limit, and even adverse reactions are caused; the related substances are still easy to exceed the specified limit after being replaced by auxiliary materials (such as hydroxypropyl methylcellulose and hydroxypropyl cellulose) containing ether bonds in the structure. In other words, when the oxycodone hydrochloride tablet adopts a wet granulation process, the related substances grow rapidly and easily exceed the specified limit. The inventor also found that oxycodone hydrochloride is prone to degrade under moist heat and oxidation conditions to produce oxycodone oxynitride and other impurities, resulting in formulations that are not quality compliant.

The invention provides a stable oxycodone hydrochloride tablet, which comprises, by weight, 10 parts of oxycodone hydrochloride, 5-25 parts of poloxamer, 70-160 parts of slow release materials, 20-80 parts of alpha-lactose and cellulose accessories, 0.5-5 parts of plasticizers and 1-5 parts of lubricants, and optionally, a coating material.

The poloxamer is a block copolymer-polyoxyethylene polyoxypropylene copolymer composed of polyoxyethylene chain segments and polyoxypropylene chain segments in different proportions. Poloxamers, which can be of different types according to different molecular weights, are selected from one or more of poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 388 and poloxamer 407, preferably poloxamer 188, poloxamer 407 or a mixture of poloxamer 188 and poloxamer 407, and most preferably poloxamer 188.

The slow release material comprises a mixture of low molecular weight polyoxyethylene and high molecular weight polyoxyethylene, wherein the content of the low molecular weight polyoxyethylene is 20-50 parts by weight, and the content of the high molecular weight polyoxyethylene is 50-110 parts by weight.

The polyoxyethylene, also called polyethylene oxide, has different types according to different molecular weights, such as WSR205, WSR1105, WSRN-12K, WSRN-60K, WSR301, WSR303 and the like, and the polyoxyethylene comprises all types and mixtures of any different types, wherein the molecular weight of the low molecular weight polyoxyethylene is less than 100 ten thousand, and can be selected from the WSR205, the WSR1105 and mixtures thereof, and is preferably the WSR1105; the high molecular weight polyoxyethylene has a molecular weight of more than 100 ten thousand and may be selected from the group consisting of WSRN-12K, WSRN-60K, WSR301, WSR303 and mixtures thereof, preferably WSRN-60K.

In the oxycodone hydrochloride tablet, the dosage of the cellulose auxiliary material is less than or equal to that of alpha-lactose, preferably, the ratio of the cellulose auxiliary material to the alpha-lactose is 1: 1 to 1: 5, and more preferably 1: 1 to 1: 4.

The cellulose auxiliary material is selected from one or more of cellulose acetate, hydroxypropyl methylcellulose, powdery cellulose and microcrystalline cellulose, wherein microcrystalline cellulose is preferred, and microcrystalline cellulose PH101 is most preferred.

The plasticizer is selected from one or more of polyethylene glycol 4000, 6000, 8000 and 10000, preferably polyethylene glycol 6000.

The lubricant is selected from any one or more of magnesium stearate, superfine silica powder, sodium fumarate stearate and talcum powder, and is preferably magnesium stearate.

The coating material is gastric soluble coating material.

In some preferred embodiments, the tablet contains oxycodone hydrochloride 10 parts by weight, poloxamer 8 parts by weight, sustained release material 130 parts by weight, microcrystalline cellulose 15 parts by weight, alpha-lactose 30 parts by weight, plasticizer 4 parts by weight, and lubricant 3 parts by weight; preferably, the slow release material is 40 parts by weight of low molecular weight polyethylene oxide and 90 parts by weight of high molecular weight polyethylene oxide; or

In some preferred embodiments, the tablet contains oxycodone hydrochloride 10 parts by weight, poloxamer 12 parts by weight, sustained-release material 120 parts by weight, microcrystalline cellulose 10 parts by weight, alpha-lactose 40 parts by weight, plasticizer 4 parts by weight, and lubricant 3 parts by weight; preferably, the slow release material is 30 parts by weight of low molecular weight polyoxyethylene and 90 parts by weight of high molecular weight polyoxyethylene; or

In some preferred embodiments, the tablet contains oxycodone hydrochloride 10 parts by weight, poloxamer 20 parts by weight, sustained release material 113 parts by weight, microcrystalline cellulose 25 parts by weight, alpha-lactose 25 parts by weight, plasticizer 5 parts by weight, and lubricant 2 parts by weight; preferably, the slow release material is 45 parts by weight of low molecular weight polyoxyethylene and 68 parts by weight of high molecular weight polyoxyethylene;

wherein the tablet is prepared by the following method:

1) Evenly mixing oxycodone hydrochloride, alpha-lactose, a plasticizer, a first part of sustained-release material and poloxamer and then melting to obtain a molten mixture;

2) Cooling and crushing the molten mixture, adding a second part of slow-release material, cellulose auxiliary materials and a lubricant into the obtained crushed particles, uniformly mixing, and tabletting to obtain plain tablets;

3) Optionally coating the plain tablets with a coating material of the gastric soluble type to obtain film coated tablets.

The invention also provides a preparation method of the stable oxycodone hydrochloride tablet, which comprises the following steps:

1) Crushing oxycodone hydrochloride serving as a main medicine, wherein the granularity of the crushed main medicine is more than or equal to 10 microns and less than or equal to D90 and less than or equal to 50 microns;

2) Uniformly mixing oxycodone hydrochloride serving as a main medicine, alpha-lactose, a plasticizer, a first part of sustained-release material and poloxamer to obtain mixed powder;

3) Melting the mixed powder of the step 2) to obtain a molten mixture;

4) Cooling the molten mixture and then crushing to obtain crushed particles;

5) Adding the obtained crushed particles into the second part of sustained-release material, cellulose auxiliary materials and lubricant, uniformly mixing to obtain total mixed powder, and tabletting to obtain plain tablets;

6) The plain tablets are optionally coated with a gastric-soluble coating material to obtain film-coated tablets.

In some embodiments, the comminution of oxycodone hydrochloride is performed using a jet mill.

In some embodiments, the melting may be performed using any of melt granulation, melt extrusion, or melt molding.

In some embodiments, the granulated mixture is obtained by a twin screw extruder; preferably, the extrusion parameters are: the minimum value of the feeding conveying section is 60 ℃, the maximum value is 75 ℃, the minimum value of the mixing and granulating section is 1, the temperature of the maximum value is 65 ℃, the temperature of the minimum value of the conveying section is 80 ℃, the temperature of the maximum value of the conveying section is 90 ℃, the temperature of the maximum value of the mixing and granulating section is 2, the temperature of the minimum value of the conveying section is 90 ℃, the temperature of the maximum value of the conveying section is 100 ℃, the temperature of the minimum value of the conveying section is 95 ℃, the temperature of the maximum value of the conveying section is 105 ℃, the extrusion temperature is 60-105 ℃, the feeding speed is set to be 5-80%, and the rotating speed of the screw is set to be 200-700 rpm.

In some embodiments, the particulate mixture is passed through a 30 mesh screen after being pulverized.

In some embodiments, the gastric coating material is

Compared with the prior art, the invention has the following beneficial technical effects:

(1) The stability of the oxycodone hydrochloride tablet is enhanced, the degradation of the main drug is reduced, related substances conform to corresponding specified limits, and the detection value is lower, particularly the detection value of oxycodone nitric oxide is extremely small or not detected;

(2) The oxycodone hydrochloride serving as the main drug is uniformly dispersed in the tablet, so that the tablet has better content uniformity;

(3) The sustained and controlled release effect is obvious, and the phenomenon of drug burst is avoided;

(4) The preparation method of the invention effectively reduces the higher temperature required by the melting process, and is beneficial to the stability of auxiliary materials with lower melting points in the composition preparation.

Additional features and advantages of the present application will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by the practice of the present application. Other advantages of the present application may be realized and attained by the instrumentalities and combinations particularly pointed out in the specification and the drawings.

Drawings

The accompanying drawings are included to provide an understanding of the present disclosure and are incorporated in and constitute a part of this specification, illustrate embodiments of the disclosure and together with the examples serve to explain the principles of the disclosure and not to limit the disclosure.

FIG. 1 is a flow chart of the process for preparing the stable oxycodone hydrochloride tablets of the example.

Detailed Description

Hereinafter, embodiments of the present invention will be described in detail in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be noted that the embodiments and features of the embodiments in the present application may be arbitrarily combined with each other without conflict.

Material

Example 1

Comprises the following components:

name (R)	mg/unit
		Oxycodone hydrochloride	10
Poloxamer 188	8
		Polyoxyethylene WSR1105	40
Polyoxyethylene N-60K	90
		Microcrystalline cellulose PH101	15
Alpha-lactose	30
		Polyethylene glycol 6000	4
Magnesium stearate	3
		In total	200

The preparation method comprises the following steps:

1) Starting an air flow grinder, setting crushing parameters, adding the main medicine for crushing after the set pressure is stable, wherein the granularity of the crushed raw material is more than or equal to 10 microns and less than or equal to D90 and less than or equal to 50 microns;

2) Uniformly mixing main drugs of oxycodone hydrochloride, alpha-lactose, polyethylene glycol 6000, polyoxyethylene WSR1105 and poloxamer 188 for 15min (the rotating speed of a stirring paddle is 120rpm, and the rotating speed of a cutter is 300 rpm);

3) The twin-screw extruder was started and the temperatures in the different zones were set as follows: minimum 60 ℃ and maximum 75 ℃ in the feed conveying section, minimum 65 ℃ and maximum 80 ℃ in the mixed granulation section 1, minimum 80 ℃ and maximum 90 ℃ in the conveying section, minimum 90 ℃ and maximum 90 ℃ in the mixed granulation section 2, maximum 100 ℃ and minimum 95 ℃ and maximum 105 ℃ in the conveying section (Pharma 11 twin-screw extruder by Thermo Fisher);

4) The extrusion temperature of the double-screw extruder is 60-105 ℃, the feeding speed is set to be 5-80%, the rotating speed of the screw is set to be 200-700 rpm, the mixed powder in the step 2) is added after the temperature and the rotating speed reach set values and are stable, and the mixture is melted and extruded to obtain a granular mixture;

5) Cooling the granular mixture, crushing, and sieving the crushed granules by a 30-mesh sieve;

6) Adding the obtained granules sieved by a 30-mesh sieve into polyoxyethylene N-60K, microcrystalline cellulose and magnesium stearate, putting into a mixer, uniformly mixing at the mixing speed of 15rpm for 20min to obtain total mixed powder, and tabletting the total mixed powder by using a rotary tablet press;

7) A medicinal film-coated premix powder (gastric-soluble type) (trade name:

solid content of 15%) to obtain film coated tablet.

Example 2

Consists of the following components:

name(s)	mg/unit
		Oxycodone hydrochloride	10
Poloxamer 188	12
		Polyoxyethylene WSR1105	30
Polyoxyethylene N-60K	90
		Microcrystalline cellulose PH101	10
Alpha-lactose	40
		Polyethylene glycol 6000	4
Magnesium stearate	4
		In total	200

The preparation method comprises the following steps:

1) Starting the jet mill, setting crushing parameters, adding the main medicine for crushing after the set pressure is stable, wherein the granularity of the crushed raw material is not less than 10 microns and not more than D90 and not more than 50 microns;

2) Uniformly mixing main drugs of oxycodone hydrochloride, alpha-lactose, polyethylene glycol 6000, polyoxyethylene WSR1105 and poloxamer 188 for 15min (the rotation speed of a stirring paddle is 120rpm, and the rotation speed of a cutter is 300 rpm);

3) The twin-screw extruder was started and the temperatures in the different zones were set as follows: a minimum value of 60 ℃ and a maximum value of 75 ℃ in the feeding and conveying section, a minimum value of 65 ℃ and a maximum value of 80 ℃ in the mixing and granulating section 1, a minimum value of 80 ℃ and a maximum value of 90 ℃ in the conveying section, a minimum value of 90 ℃ and a maximum value of 100 ℃ in the mixing and granulating section 2, a minimum value of 95 ℃ and a maximum value of 105 ℃ in the conveying section (Pharma 11 twin-screw extruder manufactured by Thermo Fisher);

7) A pharmaceutical film-coated premix powder (gastric soluble type) (trade name:

solid content of 15%) were coated to obtain film-coated tablets.

Example 3

Consists of the following components:

name (R)	mg/unit
		Oxycodone hydrochloride	10
Poloxamer 188	20
		Polyoxyethylene WSR1105	45
Polyoxyethylene N-60K	68
		Microcrystalline cellulose PH101	25
Alpha-lactose	25
		Polyethylene glycol 6000	5
Magnesium stearate	2
		Total of	200

The preparation method comprises the following steps:

2) Adding oxycodone hydrochloride, alpha-lactose, polyethylene glycol 6000, polyoxyethylene WSR1105 and poloxamer 188 as main ingredients into a wet granulator, and uniformly mixing for 15min (the rotating speed of a stirring paddle is 120rpm, and the rotating speed of a cutter is 300 rpm);

4) The extrusion temperature of the double-screw extruder is 60-105 ℃, the feeding speed is set to be 5-80%, the rotating speed of the screw is set to be 200-700 rpm, and after the temperature and the rotating speed reach set values and are stable, the mixed powder in the step 2) is added, and is melted and extruded to obtain a granular mixture;

solid content of 15%) to obtain film coated tablet.

Comparative example 1

In order to facilitate the description of the formulation composition and the melting technique of the present composition for improving stability of oxycodone hydrochloride tablets, a key stabilizing effect is played. Comparative examples of the process for preparing a commercial oxycodone hydrochloride sustained-release tablet are provided below as compared with examples of the present invention.

Comprises the following components:

materials:

name (R)	Model number	Source (manufacturer)
			Oxycodone hydrochloride	NA	Macfarlan Smith Limited
Butylated hydroxytoluene	NA	JIANGXI ALPHA HI-TECH PHARMACEUTICAL Co.,Ltd.
			Titanium dioxide	NA	HUNAN JIUDIAN HONGYANG PHARMACEUTICAL Co.,Ltd.
Polyethylene oxide	WSR1105、WSRN-60K	Specialty Products US LLC
			Hydroxypropyl cellulose	NA	Ashland Specialty Ingredients G.P.
Polyethylene glycol	6000	Hunan Er-Kang Pharmaceutical Co.,Ltd.
			Magnesium stearate	NA	HUZHOU ZHANWANG PHARMACEUTICAL Co.,Ltd.

The preparation method comprises the following steps:

1) Starting an air flow grinder to grind the main drugs, wherein the granularity of the ground raw materials is less than or equal to 10 mu m and less than or equal to D90 and less than or equal to 50 mu m;

2) Preparing hydroxypropyl cellulose into a binder solution with the concentration of 5%; putting main drug, butyl Hydroxy Toluene (BHT), titanium dioxide, polyoxyethylene WSR1105 and polyethylene glycol 6000 into a wet granulator, mixing for 5min, adding adhesive solution, and performing wet granulation;

3) Putting wet granules subjected to wet granulation into a fluidized bed for drying, setting the drying temperature to be 60 ℃, stopping drying when the moisture of the material is below 2%, collecting the dried granules, and sieving the granules with a sieve with the aperture of 1.0mm for granulation;

4) Adding polyoxyethylene WSR N-60K and magnesium stearate into the obtained granules sieved by a 30-mesh sieve, adding into a mixer, and uniformly mixing for 20min at the mixing speed of 15 rpm; tabletting the total mixed powder by using a rotary tablet machine;

5) And (3) preparing the coating premixed powder into medicinal film coating premixed powder (gastric soluble type) with the solid content of 15 percent, and coating the plain tablets obtained by tabletting to obtain the film coated tablets.

Comparative example 2

Consists of the following components:

The preparation method comprises the following steps:

2) Preparing poloxamer and polyethylene glycol 6000 into 4% adhesive solution; putting main drug, polyoxyethylene WSR1105, microcrystalline cellulose and alpha-lactose into a wet granulator, and adding an adhesive solution for granulation;

3) After the granulation is finished, stopping drying when the moisture content of the material is below 2%, collecting the dried particles, and sieving the particles through a sieve with the aperture of 1.0mm to perform granulation;

4) Adding polyoxyethylene WSR N-60K and magnesium stearate into the obtained granules sieved by the 30-mesh sieve, putting into a mixer, mixing at the mixing speed of 15rpm, and uniformly mixing for 20min; tabletting the total mixed powder by using a rotary tablet machine;

5) And (3) preparing the coating premixed powder into medicinal film coating premixed powder (gastric soluble type) with the solid content of 15%, and coating the plain tablets obtained by tabletting to obtain the film coated tablets.

Comparative example 3: the polyvidone is prepared by wet granulation

Comprises the following components:

crospovidone was purchased from ISP corporation; povidone K30 was purchased from lazhou expeditions pharmaceutical limited.

The preparation method comprises the following steps:

2) Preparing povidone K30 into a 5% adhesive solution; putting main drug, polyoxyethylene WSR1105, butylhydroxytoluene (BHT), titanium dioxide, polyethylene glycol 6000 and crospovidone into a wet granulator, and adding adhesive solution for granulation;

3) After granulation, putting into a fluidized bed for drying, stopping drying when the moisture of the material is below 2%, collecting the dried particles, and sieving the particles by a sieve with the aperture of 1.0mm for granulation;

Measurement method

[ MEASUREMENT OF CONTENT ]

Measuring by high performance liquid chromatography (China pharmacopoeia 2020 edition four-part general regulation 0512).

Chromatographic conditions and system applicability test: chromatographic column using octadecylsilane chemically bonded silica as filler; dipotassium phosphate solution (6.8 g dipotassium phosphate is dissolved in 1000mL of ultrapure water, 1.2mL of triethylamine is added, the pH is adjusted to 3.0 by phosphoric acid, and the obtained methanol-tert-butyl methyl ether (800: 200: 5) is filtered to be used as a mobile phase; the detection wavelength is 230nm; the column temperature was 60 ℃ and the flow rate was 1ml/min. And taking the reference solution as a system applicability solution, injecting the system applicability solution into a liquid chromatograph, continuously injecting for 5 times, and recording a chromatogram, wherein the RSD (dominant peak area) of the main peak cannot exceed 2.0%.

The determination method comprises the following steps: taking pH1.2 hydrochloric acid and 0.2% sodium chloride solution as diluents (taking 1000mL of purified water, adding 7mL of hydrochloric acid and 2.0g of sodium chloride, dissolving and uniformly mixing to obtain the solution), adding 300mL of diluents into a 500mL measuring flask, placing on a shaking table at 170rpm, taking 5 tablets of the product, adding into the measuring flask, carrying out ultrasonic treatment for 10min, shaking uniformly after the diluent is subjected to constant volume, and filtering to obtain a test solution; taking a proper amount of oxycodone hydrochloride reference substance, precisely weighing, adding a diluent to dissolve, and quantitatively diluting to prepare a solution containing about 0.1mg of oxycodone hydrochloride per 1mL, wherein the solution is used as a reference substance solution.

And (3) respectively injecting the test solution and the reference solution into a liquid chromatograph, recording a chromatogram, and calculating the content of the product by peak area according to an external standard method.

Wherein, the 'A supply' is the main peak area of the test solution; the W pair is the sample weighing of a reference substance; "P" is the reference content; the 'A pair' is the main peak area of the reference solution; the 'V pairs' are the dilution times of the reference substances; the V supply is the dilution factor of the test sample.

[ EYE DISSOLUTION ]

Taking the product, according to a dissolution and release determination method (0931 first method of the general rule of four parts of the 2020 edition of Chinese pharmacopoeia), taking 900mL of hydrochloric acid with pH of 1.2 and 0.2% sodium chloride solution (obtained by taking 1000mL of purified water, adding 7mL of hydrochloric acid and 2.0g of sodium chloride, dissolving and mixing uniformly) as a dissolution medium, rotating at 100rpm, operating according to the method, taking 1.5mL of solution after 1, 4 and 8 hours, filtering, and taking the subsequent filtrate as a test solution; taking a proper amount of oxycodone hydrochloride reference substances, precisely weighing, adding a diluent to dissolve, quantitatively diluting to prepare a solution containing 0.1mg in each 1mL, and detecting the dissolution amount under the same content measurement item. The elution amount of each tablet was calculated by peak area according to the external standard method.

[ related substances ]

If an impurity peak exists in a chromatogram of a test solution, the oxycodone nitric oxide is not more than 0.5 percent, other maximum single impurities are not more than 0.5 percent, and the total impurities are not more than 2.0 percent according to the calculation of a self-contrast method; other impurities (0.03%) were ignored which were less than 0.06 times the area of the main peak of the control solution.

Herein, "other maximum single impurities" refers to "other maximum known single impurities", and the sum of the other maximum known single impurities and other unknown single impurities (the detected value of the unknown single impurities is extremely low, and may not be calculated, and there are more peak positions, which cannot be listed one by one) is the total impurities. Herein, oxycodone nitroxide is the sole test term, not counted in total impurities.

The detection method of the related substances comprises the following steps:

(1) Solution preparation

Blank solvent: diluting agent-pH1.2 hydrochloric acid and 0.2% sodium chloride solution (1000 ml purified water is added with 7ml hydrochloric acid and 2.0g sodium chloride to dissolve and mix uniformly to obtain)

Test solution: taking hydrochloric acid with pH of 1.2 and 0.2% sodium chloride solution as diluents, adding 150mL of diluents into a 250mL measuring flask, placing on a shaking table at 170rpm, adding 5 tablets of the product into the measuring flask, shaking until the solution becomes homogeneous, performing ultrasonic treatment for 10min, shaking up after the diluent is subjected to constant volume, centrifuging, and taking supernatant as a test solution;

control solution: 1ml of supernatant of the test solution was measured precisely and diluted to 200ml with a diluent as a control solution.

System applicability solution (sensitivity solution): 2ml of the control solution is transferred and placed in a 10ml measuring flask, and the volume is determined by using a diluent and shaken up to be used as a system applicability solution.

(2) Chromatographic conditions

A chromatographic column: octadecylsilane chemically bonded silica is used as a filling agent;

column temperature: 30 ℃;

flow rate: 1ml/min

Detector wavelength: 230m;

sample introduction volume: 50u1

Mobile phase: taking 0.77g/L ammonium acetate solution as a mobile phase A and methanol as a mobile phase B;

the elution procedure was as follows:

time (min)	Mobile phase A (% by volume)	Mobile phase B (% by volume)
			0	70	30
5	70	30
			20	25	75
40	25	75
			48	70	30
52	70	30

(3) Calculating out

And precisely measuring 50ul of each of the system applicability solution, the test sample solution and the control solution, injecting into a liquid chromatograph, recording a chromatogram, and calculating according to a self-control method.

The retention time of oxycodone chromatographic peak is about 29min, and the signal-to-noise ratio is more than or equal to 10.

If an impurity peak exists in a chromatogram of a test solution, wherein the relative retention time (based on an oxycodone peak) of oxycodone oxynitride is about 0.28, the relative retention time is calculated according to a self-comparison method, and the formula is as follows:

wherein, ax: peak areas of impurities in a chromatogram of the test solution; as: the main peak area of the chromatogram of the control solution; f: impurity relative correction factor, wherein the relative correction factor of oxycodone nitric oxide is 0.8, and the relative correction factor of other impurities is 0.1.

Quality detection

The quality tests were carried out for each of examples 1, 2, 3 and comparative example 1, and the test results are shown in Table-1.

TABLE-1: quality test results of each of examples 1, 2, 3 and comparative example 1

As can be seen from the test results of the examples, the oxycodone hydrochloride tablets prepared by the formula and the melting process provided by the invention have better content, dissolution rate, related substances and the like than those of the products on the market and have excellent quality stability.

Evaluation method

[ HIGH-TEMPERATURE TEST ] the sample was exposed and dried at a constant temperature of 60 + -2 deg.C, and sampled for 0, 10, and 30 days. The content, dissolution and related substances are respectively detected, and the detection results are shown in the table-2.

TABLE-2: examples 1, 2 and 3 and comparative example 1, the content, dissolution rate and related substance detection results are detected

[ ILLUMINATION TEST ] the sample was exposed and placed under the conditions of 4500Lx + -500 Lx for sampling and detection at 0, 10, and 30 days, respectively. The content, dissolution and related substances are respectively detected, and the detection results are shown in Table-3.

TABLE-3: examples 1, 2 and 3 and comparative example 1 are used for detecting content, dissolution rate and related substance detection results

[ HIGH-HUMIDITY TEST ] A sample is exposed at 25 ℃. + -. 2 ℃/RH 90. + -. 5%, and is sampled and detected for 0, 10 and 30 days respectively. The content, dissolution and related substances are respectively detected, and the detection results are shown in the table-4.

TABLE-4: examples 1, 2 and 3 and comparative example 1 are used for detecting content, dissolution rate and related substance detection results

The tablet was examined for the influence factor, and the experiment showed that the nitrogen oxides of the related substances in the comparative examples exceeded the specified limit after 30 days under high temperature and light conditions, and the detection values were large and close to each other even though the nitrogen oxides were not exceeded under high humidity conditions. Therefore, when the wet granulation is adopted according to the same auxiliary materials disclosed in the specifications of commercial products of OxyContin (sustained release), related substances exceed the limit and the detection value is larger.

According to the comparative detection results, the oxycodone hydrochloride tablet prepared by the prescription and the melting process provided by the invention has excellent storage stability, is exposed and placed under severe environments (high temperature, illumination and high humidity) for 10 and 30 days, has no change in dissolution rate, related impurities and content compared with 0 day, and has good stability.

[ accelerated test ] the samples were placed at 60. + -. 2 ℃/RH 90. + -. 5% and sampled for measurement at 0, 1, 3, and 6 months, respectively. The content, dissolution and related substances are respectively detected, and the detection results are shown in Table-5.

TABLE-5: examples 1, 2 and 3 and comparative example 1, the content, dissolution rate and related substance detection results are detected

As can be seen from the table above, when the oxycodone hydrochloride tablet is placed for 1, 3 and 6 months under an accelerated condition, the growth of related substances is obvious in comparative example 1, and the content, the dissolution rate and the related substances of the oxycodone hydrochloride tablet prepared by the formula and the melting process provided by the invention have no obvious change compared with 0 day, so that the oxycodone hydrochloride tablet has good stability; the prepared composition has good stability.

[ LONG-TERM TEST ] the samples were placed at 25 ℃. + -. 2 ℃/RH 60. + -. 10% and sampled for determination at 3, 6, 9, 12, 18, 24, 36 months, respectively, to compare with the results of the 0-day test. The content, dissolution and related substances are respectively detected, and the detection results are shown in Table-6.

TABLE-6: examples 1, 2 and 3 and comparative example 1, the content, dissolution rate and related substance detection results are detected

As can be seen from the table, the related substances in comparative example 1 increase more obviously after being placed for 3, 6, 9, 12, 18, 24 and 36 months under long-term conditions, but the content, dissolution rate and related substances of the oxycodone hydrochloride tablet prepared by the formula and the melting process provided by the invention have no significant change compared with 0 day, and the composition stability is good.

The stability and dissolution results of the tablets obtained by wet granulation of comparative example 2 are shown in the following table.

TABLE-7: dissolution rate and related substance test results of comparative example 2

And (4) conclusion: when the same components are granulated by a wet method, the detection value of related substances is close to the limit only in 0 day, and the dissolution is fast, so that the risk of burst release of the medicine exists; after the investigation, the related substances exceed the limit requirements, and the quality does not meet the requirements.

TABLE-8 results of examining substances related to comparative example 3

And (4) conclusion: all related substances are out of limits.

Experiments show that compared with the commercially available products, the stable oxycodone hydrochloride tablet prepared by the invention has no or very small detection value of oxycodone nitric oxide after stability inspection, and has very small detection values of other related substances. The tablet and the preparation method provided by the invention well solve the problem of instability caused by obvious increase of related substances in the production process and the storage process of the preparation, improve the product quality, prolong the effective period of the product, and improve the safety and stability of the tablet.

The present invention is illustrated by the above examples for oxycodone hydrochloride tablets, but the present invention is not limited to the above detailed process, i.e. it is not meant to imply that the present invention has to be carried out in dependence on the above detailed process. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.

Claims

1. A stable oxycodone hydrochloride tablet, wherein the tablet comprises, by weight, 10 parts of oxycodone hydrochloride, 5-25 parts of poloxamer, 70-160 parts of slow release materials, 20-80 parts of alpha-lactose and cellulose accessories, 0.5-5 parts of plasticizers, 1-5 parts of lubricants and optionally coating materials.

2. The tablet according to claim 1, wherein the poloxamer is selected from one or more of poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 388 and poloxamer 407, preferably poloxamer 188, poloxamer 407 or a mixture of poloxamer 188 and poloxamer 407, most preferably poloxamer 188;

the slow release material is a mixture of low molecular weight polyoxyethylene and high molecular weight polyoxyethylene; preferably, the content of the low molecular weight polyoxyethylene is 20-50 parts by weight, and the content of the high molecular weight polyoxyethylene is 50-110 parts by weight;

the cellulose auxiliary material is selected from one or more of cellulose acetate, hydroxypropyl methylcellulose, powdery cellulose and microcrystalline cellulose, preferably microcrystalline cellulose, and most preferably microcrystalline cellulose PH101; wherein the weight ratio of the cellulose auxiliary material to the alpha-lactose is 1: 1 to 1: 5, and more preferably 1: 1 to 1: 4;

the plasticizer is any one or more of polyethylene glycol 4000, 6000, 8000 and 10000, preferably polyethylene glycol 6000;

the lubricant is any one or more selected from magnesium stearate, superfine silica powder, sodium fumarate stearate and talcum powder, and preferably magnesium stearate;

the coating material is gastric soluble coating material.

3. The tablet according to claim 2, wherein the low molecular weight polyethylene oxide has a molecular weight of less than 100 ten thousand, preferably WSR205, WSR1105 and mixtures thereof, most preferably WSR1105; the high molecular weight polyoxyethylene has a molecular weight of 100 ten thousand or more, preferably WSRN-12K, WSRN-60K, WSR301, WSR303 and mixtures thereof, and most preferably WSRN-60K.

4. The tablet according to claim 3, wherein the tablet comprises oxycodone hydrochloride 10 parts by weight, poloxamer 8 parts by weight, sustained-release material 130 parts by weight, microcrystalline cellulose 15 parts by weight, alpha-lactose 30 parts by weight, plasticizer 4 parts by weight, and lubricant 3 parts by weight; preferably, the slow release material is 40 parts by weight of low molecular weight polyethylene oxide and 90 parts by weight of high molecular weight polyethylene oxide; or alternatively

The tablet comprises 10 parts by weight of oxycodone hydrochloride, 12 parts by weight of poloxamer, 120 parts by weight of slow-release material, 10 parts by weight of microcrystalline cellulose, 40 parts by weight of alpha-lactose, 4 parts by weight of plasticizer and 3 parts by weight of lubricant; preferably, the slow release material is 30 parts by weight of low molecular weight polyethylene oxide and 90 parts by weight of high molecular weight polyethylene oxide; or

The tablet comprises 10 parts by weight of oxycodone hydrochloride, 20 parts by weight of poloxamer, 113 parts by weight of slow-release material, 25 parts by weight of microcrystalline cellulose, 25 parts by weight of alpha-lactose, 5 parts by weight of plasticizer and 2 parts by weight of lubricant; preferably, the slow release material is 45 parts by weight of low molecular weight polyoxyethylene and 68 parts by weight of high molecular weight polyoxyethylene.

5. The tablet of any one of claims 1-4, wherein the tablet is prepared by the process of:

evenly mixing oxycodone hydrochloride, alpha-lactose, a plasticizer, a first part of sustained-release material and poloxamer and then melting to obtain a molten mixture;

cooling and crushing the molten mixture, adding a second part of slow-release material, cellulose auxiliary materials and a lubricant into the obtained crushed particles, uniformly mixing, and tabletting to obtain plain tablets;

optionally, coating the tablet with gastric-soluble coating material to obtain film-coated tablet.

6. The tablet of claim 5, wherein the particle size of oxycodone hydrochloride prior to melt mixing is 10 μm or less and D90 or less and 50 μm or less.

7. The tablet of claim 5, wherein the first portion of sustained release material is a low molecular weight polyethylene oxide; the second part of the slow release material is high molecular weight polyoxyethylene.

8. A preparation method of a stable oxycodone hydrochloride tablet, wherein the tablet comprises 10 parts by weight of oxycodone hydrochloride, 5-25 parts by weight of poloxamer, 70-160 parts by weight of slow release material, 20-80 parts by weight of alpha-lactose and cellulose accessories, 0.5-5 parts by weight of plasticizer and 1-5 parts by weight of lubricant, and optionally a coating material;

the method comprises the following steps:

2) Uniformly mixing oxycodone hydrochloride, alpha-lactose, a plasticizer, a first part of sustained-release material and poloxamer serving as main medicines to obtain mixed powder;

3) Melting the mixed powder of the step 2) to obtain a molten mixture;

4) Cooling the molten mixture and then crushing to obtain crushed particles;

9. The method according to claim 8, wherein the first portion of slow release material is a low molecular weight polyethylene oxide having a molecular weight of less than 100 ten thousand, preferably WSR205, WSR1105 and mixtures thereof, most preferably WSR1105; the second part of sustained-release material is high molecular weight polyoxyethylene with molecular weight of 100 ten thousand or more, preferably WSRN-12K, WSRN-60K, WSR301, WSR303 and their mixture, and most preferably WSRN-60K.

10. The method according to claim 8, wherein the poloxamer is selected from one or more of poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 388 and poloxamer 407, preferably poloxamer 188, poloxamer 407 or a mixture of poloxamer 188 and poloxamer 407, most preferably poloxamer 188;

the lubricant is any one or more selected from magnesium stearate, superfine silica gel powder, sodium fumarate stearate and talcum powder, and is preferably magnesium stearate; and is

The lubricant is magnesium stearate.

11. The method of any of claims 8-10, wherein the granulated mixture is passed through a 30 mesh screen after being pulverized.