CN115702888A - Oxycodone hydrochloride osmotic pump sustained-release tablet and preparation method thereof - Google Patents
Oxycodone hydrochloride osmotic pump sustained-release tablet and preparation method thereof Download PDFInfo
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Abstract
The invention relates to the field of pharmaceutical preparations, and particularly provides an abuse-proof oxycodone hydrochloride sustained-release tablet and a preparation method thereof. The sustained-release tablet preparation is applied to the abuse prevention field through a controlled-release film coating technology, the preparation is difficult to damage, oxycodone hydrochloride in the preparation is difficult to extract, the abuse prevention of opioid drugs is facilitated, the drug release is stable, a better in-vivo pharmacokinetic and in-vitro release curve is realized, and the use amount of the drugs can be reduced. The preparation method of the sustained-release tablet is simple and easy in process, creatively uses a process route of firstly coating and then curing, and solves the technical defect of curing and sticking the tablet.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to an abuse-proof oxycodone hydrochloride sustained release tablet and a preparation method thereof.
Background
Oxycodone hydrochloride is an anesthetic, is a semisynthetic opioid extracted from alkaloid thebaine, belongs to a strong opioid, is mainly used as a first-line treatment of moderate and severe pain, is the treatment of cancer pain at the earliest and is developed to the treatment of chronic non-cancer pain later. The drug is first published in Germany in 1917, has been clinically applied for more than 80 years as a potent analgesic, is a controlled variety listed in United nations' Single convention on narcotics in 1961, and is also classified into the controlled range of narcotics in China.
The conventional dosage form of oxycodone hydrochloride has two major disadvantages: 1. being susceptible to abuse, oxycodone is a full agonist of the opioid receptor, has similar abuse liability as morphine, belongs to narcotic analgesic drugs, and has abuse potential as morphine and other opioid drugs for analgesia. 2. The half life is 3-4h, so the medicine needs to be taken about 4-6 times a day.
The trade name is
Oxycodone hydrochloride sustained release tablets (developed by Purdue) have been approved by the FDA for commercialization. They adopt the skeleton (matrix) type slow-release tablet technology, and utilize the hydrophilic gel layer formed by matrix in water to control the drug release. From the product patents (US 8894988, US 7674800), the specification emphasizes that the molecular weight and content of polyoxyethylene in the formulation act in the formulation, the polyoxyethylene can be melted in the heating process, and forms a high-hardness state after being cooled again, and the polyoxyethylene has good capability of preventing physical damage and chemical damage. In the specification, the curing process adopts direct addition of tablet coresAnd (4) performing heat curing, scattering magnesium stearate as an anti-adhesion agent in the curing process, and coating after the curing is completed. The design has the defects that tablet cores are easy to be sticky and deformed in the curing process, and the operation of scattering magnesium stearate is easy to cause the uneven content of magnesium stearate in each tablet, thereby influencing the quality of medicines. The method is also not beneficial to mass production and affects the production efficiency.
Patent CN 102657630A discloses a solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation comprising a composition containing at least oxycodone hydrochloride and at least about 80wt% of polyethylene oxide having a molecular weight of at least 100 ten thousand. However, this patent does not prevent abuse of the drug by the oral route and has the drawback that the time for drug administration is at least 12 hours. The invention adds a layer of controlled release film coat on the basis of keeping the polyoxyethylene matrix, which not only can keep the high hardness state of the original tablet core matrix, but also can add a damage-proof barrier for the tablet core, greatly improves the cracking force of the tablet core and has larger difficulty in damaging the tablet core. The controlled release film coating can also regulate the release of the drug, so that the release of the drug is more stable, and for opioid drugs, the failure to release the drug rapidly means the failure of abuse through an oral route. The present invention thus makes it possible to prevent abuse of the oral route to a greater extent.
Li Fang 'introduction of innovation of opium drug abuse-proof technology' discloses that oxycodone hydrochloride sustained-release tablets are added with polyethylene oxide and hydroxypropyl methyl cellulose to form a colloid in a solvent, so that the raw material drugs are prevented from being extracted by the solvent and then are used for intravenous injection. Patent CN 111465396A discloses a morphine sulfate solid oral sustained release drug formulation, which comprises morphine sulfate, 55% -95% polyethylene oxide with molecular weight of 60-300 ten thousand, 0.1% -5% lubricant preferably magnesium stearate, and 0.1% -2.5% glidant preferably colloidal silicon dioxide. However, the document and patent still cannot solve the abuse of drugs by oral route.
Therefore, there is a need for further improvement on the prior art, so that the oxycodone hydrochloride sustained release tablet preparation has better abuse prevention and sustained release effects, can effectively prevent drug abuse in oral routes, can reduce the frequency of drug use, improve the drug release behavior, and has better sustained release effect, thereby making the use of oxycodone hydrochloride safer and more effective.
Disclosure of Invention
Aiming at the technical problems, the invention provides an improved oxycodone hydrochloride sustained release tablet preparation, which is an abuse-resistant oxycodone hydrochloride sustained release tablet with good quality and a preparation method thereof.
The invention provides an oxycodone hydrochloride sustained release tablet which comprises a tablet core, a controlled release film coat and a film coat, wherein the tablet core comprises the following components in percentage by weight of the tablet core:
the weight increment of the controlled-release film coat is 1-20% of the weight of the tablet core; the weight increment of the film coat is 1-15% of the weight of the tablet core.
In the present invention, as one embodiment, the release modifier is used in an amount of 50 to 95%, preferably 80 to 95%, by weight of the tablet core.
As an embodiment, the release modifier of the present invention is selected from polyoxyethylene, wherein the polyoxyethylene is polyoxyethylene having a molecular weight of 10 ten thousand or more, preferably polyoxyethylene having a molecular weight of 10 ten thousand to 700 ten thousand, or a combination of polyoxyethylene having different molecular weights among the above-mentioned molecular weights of 10 ten thousand to 700 ten thousand;
illustrative examples of polyoxyethylene employed in the present invention include, but are not limited to, polyoxyethylene molecules in the same amount or a combination of polyoxyethylene molecules in10 ten thousand, 20 ten thousand, 30 ten thousand, 40 ten thousand, 50 ten thousand, 60 ten thousand, 70 ten thousand, 80 ten thousand, 90 ten thousand, 100 ten thousand, 110 ten thousand, 120 ten thousand, 130 ten thousand, 140 ten thousand, 150 ten thousand, 160 ten thousand, 170 ten thousand, 180 ten thousand, 190 ten thousand, 200 ten thousand, 210 ten thousand, 220 ten thousand, 230 ten thousand, 240 ten thousand, 250 ten thousand, 260 ten thousand, 270 ten thousand, 280 ten thousand, 290 ten thousand, 300 ten thousand, 310 ten thousand, 320 ten thousand, 330 ten thousand, 340 ten thousand, 350 ten thousand, 360 ten thousand, 370 ten thousand, 380 ten thousand, 390 ten thousand, 400 ten thousand, 410 ten thousand, 420 ten thousand, 430, 440 ten thousand, 450 ten thousand, 460 ten thousand, 470 ten thousand, 480 ten thousand, 490 ten thousand, 500 ten thousand, 510 ten thousand, 520 ten thousand, 530 ten thousand, 540 ten thousand, 550 ten thousand, 560, 570 ten thousand, 580, 590 ten thousand, 600, 690, 670, 700 thousand, or 700 thousand.
As one embodiment, when polyoxyethylene having a single molecular weight is used, the release modifier of the present invention is selected from polyoxyethylene having a molecular weight of 100 to 700 ten thousand, preferably polyoxyethylene having a molecular weight of 200 to 700 ten thousand, more preferably polyoxyethylene having a molecular weight of 400 to 700 ten thousand, and still more preferably polyoxyethylene having a molecular weight of 400 to 600 ten thousand; as one embodiment, the release modifier of the present invention is preferably polyoxyethylene having a molecular weight of 400 ten thousand, 500 ten thousand, 600 ten thousand or 700 ten thousand, and most preferably polyoxyethylene having a molecular weight of 500 ten thousand.
As an embodiment, when a combination of polyoxyethylene of different molecular weights is used, it may be a combination of polyoxyethylene of 10 to 100 ten thousand molecular weights, preferably 10 to 50 ten thousand molecular weights, and polyoxyethylene of 200 to 700 ten thousand molecular weights, preferably 400 to 700 ten thousand molecular weights, more preferably 400 to 600 ten thousand molecular weights, most preferably 500 ten thousand molecular weights; as one embodiment, in the polyoxyethylene composition having different molecular weights, 200 to 700 ten thousand molecular weight polyoxyethylene, preferably 400 to 700 ten thousand molecular weight polyoxyethylene, more preferably 400 to 600 ten thousand molecular weight polyoxyethylene, and most preferably 500 ten thousand molecular weight polyoxyethylene accounts for not less than 15%, preferably less than 50%, and more preferably not less than 80%.
As an example of an embodiment, using a composition of polyoxyethylenes of different molecular weights, the release modifier of the invention is a combination of polyoxyethylenes of 10 ten thousand molecular weight and 500 ten thousand molecular weight, wherein the weight parts ratio of the polyoxyethylenes of 10 ten thousand molecular weight to 500 ten thousand molecular weight is 15 to 110; preferably 15; as an exemplary illustration, for example, 15:115, 45:85, 80:50, or 110.
In one embodiment, the polyoxyethylene of the present invention is selected from polyoxyethylene having a molecular weight of 200 to 700 million or more; in a further embodiment of the present invention, the polyoxyethylene is a polyoxyethylene having a molecular weight of 400 to 700 ten thousand. The source of the polyoxyethylene described in the present invention is not limited at all, and may be either commercially available or prepared by a person skilled in the art in combination with the prior art.
As one embodiment, the release modifier (polyoxyethylene) of the present invention is used in an amount by weight of the tablet core, illustrative examples thereof include, but are not limited to, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90%. As one embodiment, the amount of polyoxyethylene is preferably 50% to 95% by weight of the tablet core; more preferably 80% to 95%.
In the present invention, as one of the embodiments, the amount of the binder is preferably 2% to 8%, more preferably 5% to 8%, such as 2%, 3%, 4%, 5%, 6%, 7% or 8% by weight of the tablet core, as an illustrative indication.
In the present invention, as an embodiment, the binder includes, but is not limited to, starch, dextrin, gelatin, polyethylene glycol, methylcellulose, hydroxypropylcellulose, povidone, hydroxypropylmethylcellulose, or a combination of two or more thereof, preferably hydroxypropylcellulose.
In the present invention, when the binder of the present invention is hydroxypropylcellulose, the hydroxypropylcellulose may be various types of hydroxypropylcellulose in the art, and the source thereof is not limited at all, and may be commercially available or prepared by a person skilled in the art according to the description of the prior art. As one embodiment of the invention, the binder is hydroxypropylcellulose HXF (Ashland) in an amount of 0% to 10%, preferably 2% to 8%, more preferably 5% to 8%, by weight of the tablet core, such as 2%, 3%, 4%, 5%, 6%, 7% or 8% by weight of the tablet core, as an illustrative example.
As one embodiment of the present invention, the binder may also be hypromellose or povidone.
In the present invention, as one embodiment, the lubricant is used in an amount of 0.1% to 4%, preferably 0.2% to 2%, by weight of the tablet core.
As one embodiment of the present invention, the lubricant is magnesium stearate, aerosil, talc, sodium lauryl sulfate, magnesium lauryl sulfate, or a combination of two or more thereof; magnesium stearate is preferred.
In the present invention, as one of the embodiments, the weight gain of the controlled release film coating is 1.0% to 20.0%, preferably 3.0% to 12.0%, more preferably 6.0% to 10.0% of the tablet core weight, such as 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% by way of example.
In the present invention, as one embodiment, the controlled-release film coating comprises a film-forming material, a pore-forming agent, and a coating solvent.
In the present invention, as one embodiment, the film-forming material is cellulose acetate, ethyl cellulose, ethylene-vinyl acetate copolymer, methacrylate copolymer, or a combination of two or more thereof, preferably cellulose acetate, and is used in an amount of 1% to 30%, preferably 1.0% to 10.0%, more preferably 1.0% to 6.0%, such as 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% by weight of the controlled release coating.
In an embodiment of the present invention, the pore-forming agent is polyethylene glycol (PEG 4000), povidone, hypromellose, polysorbate, sorbitan fatty acid ester, polyvinyl alcohol, lactose, or a combination of two or more of them, preferably polyethylene glycol (PEG 4000), and the amount of the pore-forming agent is 0.1% to 20%, preferably 0.5% to 15.0%, more preferably 1.0% to 10.0%, further preferably 0.5% to 5.0%, and further preferably 1.0% to 4.0% by weight of the controlled release coating, which is exemplified by 1%, 2%, 3%, or 4%.
In one embodiment of the present invention, the controlled release film coating solvent is selected from acetone, ethanol, or a combination of acetone and methanol, or a mixture of acetone and water, or a mixture of dichloromethane and ethanol, preferably acetone, and the amount of the solvent is 50% to 95%, preferably 80.0% to 95.0%, based on the weight of the controlled release film coating.
As one embodiment of the invention, the oxycodone hydrochloride sustained release tablet also comprises a controlled release film coating which has the function of controlling the smooth release of the medicine and is insoluble in water. The high-temperature resistant tablet core has good thermal stability, does not have quality change in a high-temperature curing process, and can protect the tablet core from deformation. After coating, a hard shell protective tablet core is formed, so that the tablet core is difficult to damage by external force (physical and chemical means), and oxycodone hydrochloride is extracted.
In the present invention, as one of the embodiments, the weight gain of the film coat is 1.0% to 8.0%, preferably 3.0 to 6.0%, more preferably 3.0 to 5.0% of the tablet core weight, such as 1%, 2%, 3%, 4%, 5%, 6%, 7% or 8% as an exemplary illustration.
As one embodiment of the invention, the oxycodone hydrochloride sustained release tablet further comprises a film coating, which has good water solubility, can be quickly dissolved in an aqueous solution and does not influence the dissolution and absorption of the medicine. The high-temperature resistant tablet core has good thermal stability, does not have quality change in the high-temperature curing process, and can protect the tablet core from deformation. The coating material includes, but is not limited to, a gastric-soluble type film coating material, and the specific kind can be determined by those skilled in the art according to the contents of the present invention and in combination with the common general knowledge in the art.
As one embodiment of the invention, the outer layer of the tablet core can be coated with a controlled release film coat which can regulate and control the release of the medicament, and the hard inert material can protect the tablet core, prevent the physical and chemical damages of the outside to the tablet core and reduce the abuse condition of the medicament. The controlled release film coat is coated with a film coat, the film material can adopt a gastric soluble film coat material, and the weight increment of the film coat is 1.0-8.0% of the weight of the tablet core, preferably 3.0-5.0%, such as 1%, 2%, 3%, 4%, 5%, 6%, 7% or 8% by way of exemplary illustration.
The film coating technology is well known to those skilled in the art, the process route is mature, the quality is controllable, and the film coating does not influence the in vivo and in vitro release of the drug.
The oxycodone hydrochloride sustained release tablet can be various tablet shapes commonly used in the field, such as round or irregular tablet can be selected, and the shape of the tablet is provided that the drug release is not influenced and the release residue is not generated.
The invention provides a preparation method for preparing the oxycodone hydrochloride osmotic pump sustained release tablet, which comprises the following steps:
1) Mixing the dry powder;
2) Tabletting;
3) Coating a controlled release film;
4) Film coating;
5) Curing;
6) And (6) cooling.
In the method of the present invention, as one of embodiments, the method further comprises:
1) Mixing dry powder: mixing oxycodone hydrochloride and other auxiliary materials uniformly;
2) Tabletting: tabletting by using a rotary tablet machine, controlling the hardness to be 70-160N, preferably 80-150N, more preferably 90-140N, and controlling the thickness to be 4-4.8 mm, preferably 4.1-4.5 mm;
3) Coating with a controlled release film: dissolving a film forming material and a pore-forming agent by using a controlled-release film coating solvent, and carrying out isolated coating on the tablet core by using high-efficiency coating equipment, wherein the coating temperature is controlled to be 20-50 ℃, and the weight increment of the controlled-release film coating is 1.0-20.0% of the weight of the tablet core, preferably 3.0-12.0%, and more preferably 6.0-10.0%; after coating the controlled release film, drilling a drug release hole on each of the upper and lower surfaces of the tablet by using a laser drilling machine, wherein the hole diameter is controlled to be 0.2mm to 0.8mm, preferably 0.4mm to 0.8mm, and more preferably 0.6mm to 0.8mm (for example, 0.4mm, 0.6mm, 0.7mm, etc.);
4) Film coating: dissolving a coating material by using a film coating solvent, and carrying out isolated coating on the tablet core by using high-efficiency or fluidized bed coating equipment, wherein the coating temperature is controlled to be 20-50 ℃, and the weight increment of the film coating is 1-15% of the weight of the tablet core, preferably 1.0-8.0%, more preferably 3.0-6.0%, and further preferably 3.0-5.0%;
5) Curing: curing the film-coated tablets by using a drying oven or a coating pan, wherein the curing temperature is controlled to be 60-90 ℃, and preferably 70-80 ℃; the curing time is 1 to 8 hours, preferably 2 to 5 hours;
6) And (3) cooling: cooling the cured film-coated tablets at normal temperature for 1 minute to 2 hours.
In the method of the present invention, as one embodiment, the step 1) further comprises: pouring oxycodone hydrochloride and half amount of polyoxyethylene and other auxiliary materials into a wet mixing granulator, and stirring at the rotating speed of 30-200 rpm, preferably 50-180 rpm, more preferably 110-180 rpm (which can be 110rpm, 120rpm, 130rpm, 140rpm, 150rpm, 160rpm, 170rpm and 180rpm as illustrative examples); the shearing speed is 300 to 4000rpm, preferably 1000 to 3000rpm, more preferably 2000 to 2800rpm;2700rpm, mixing for 1 min-3 min10min, preferably 2 min-6 min, more preferably 2-5 min; then adding the rest polyoxyethylene, and stirring at the rotating speed of 30-200 rpm, preferably 50-180 rpm, more preferably 110-180 rpm; the shearing speed is 300-4000 rpm, preferably 1000-3000 rpm, more preferably 2000-2800 rpm; mixing for 1min to 10min, preferably 2min to 6min, more preferably 2 to 5min.
As one embodiment, the solvent of the controlled release film coating in step 3) is selected from a solvent for the controlled release film coating selected from methanol, ethanol, acetone, dichloromethane or water, or a combination of two or more of them; in one embodiment, it is preferable that the acetone is a combination of two or more of the above solvents, and in one embodiment, the solvent is selected from the group consisting of a combination of acetone and ethanol, a combination of acetone and methanol, a mixture of acetone and water, a mixture of acetone and dichloromethane, and a mixture of dichloromethane and ethanol, and is used in an amount of 50% to 90%, preferably 60.0% to 80.0%, and more preferably 65.0% to 75.0%, by weight of the controlled release film.
The invention creatively coats a controlled release film coating layer on the outer layer of the matrix type tablet core, adds a physical barrier for the tablet core, does not change the original high hardness characteristic of the tablet core, greatly improves the cracking force of the tablet core, and further reduces the abuse possibility of the tablet core after being crushed.
The oxycodone hydrochloride sustained-release tablet comprises a tablet core, a controlled-release film coat and a film coat; the polyoxyethylene has a low melting point (65-70 ℃) and forms a high-hardness state after being melted and cooled again, so that the polyoxyethylene has good capability of preventing physical damage and chemical damage, and the sustained-release characteristic of the drug is not influenced. Therefore, the invention can effectively prevent the abuse of the preparation through a nasal inhalation route after the preparation is crushed or prevent the oxycodone hydrochloride in the preparation from being extracted, thereby reducing the abuse of the oxycodone hydrochloride and improving the medication safety.
The invention further improves the preparation process of the oxycodone hydrochloride sustained-release tablets, and the preparation process comprises the following steps:
1. because the tablet core contains a large amount of macromolecular polyoxyethylene, the polyoxyethylene can be sticky when heated, a coating pan is used for heating in the prior art, the tablet core is directly cured, and even if a large amount of magnesium stearate is added in the curing process and the rotating speed of the coating pan is increased, serious sticky tablets or deformation can be generated as a result, so that the product quality is influenced;
2. through test comparison, the inventor finds that after the tablet core is coated with the controlled release film and the film coating, the phenomenon of sticking or deformation does not occur in the curing process, and the film coating does not influence the curing effect and the release of the tablet core.
Tests and comparison show that the sustained-release tablet can realize more excellent curing effect.
The content of the invention not only can achieve better abuse-proof effect than the prior art in the aspect of abuse-proof performance, but also improves the medication safety of the medicine; the invention is more feasible in the process aspect, and solves the problems of directly curing the tablet core, sticking the tablet and deformation.
Drawings
FIG. 1: examples 1-1 to 1-5 drug release profiles;
FIG. 2: examples 2-1 to 2-3 drug release profiles;
FIG. 3: example 3-1 to 3-5 drug release profile;
FIG. 4: examples 4-6 drug release profiles;
FIG. 5: comparative example 1 to comparative example 2 drug release behavior profiles;
FIG. 6: examples 1-3 compression resistance pictures;
FIG. 7: example 3-3 compression resistance pictures;
FIG. 8: comparative example 1 compression resistance picture;
FIG. 9: comparative example 2 compression resistance picture;
FIG. 10: examples 1-3 plasma concentration-time profiles;
FIG. 11:
blood concentration-time curve diagram
Detailed Description
The present invention is further illustrated by the following examples and experimental examples, but the present invention is not limited thereto.
The pre-blended film coating materials used in the following examples are, unless otherwise specified, the stomach soluble opadry type ii available from colorron corporation (commercially available). The following examples are merely illustrative of the present invention and are not intended to limit the scope of the invention. Those skilled in the art can make appropriate changes to the technical solution without departing from the main concept and spirit of the invention, and these changes are all within the scope of the invention.
In terms of the preparation method, a suitable preparation method includes not only the following examples, but also tabletting, coating and the like techniques which are conventional in the art can be used in the present invention.
EXAMPLE 1 maturation conditions
1. Tablet core composition (mg/P)
Mixing dry powder: pouring oxycodone hydrochloride, half amount of PEO500 ten thousand and other auxiliary materials into a wet mixing granulator, stirring at the rotating speed of 180rpm, shearing at the rotating speed of 2700rpm, and mixing for 3min; adding 500 million of the residual PEO, stirring at the rotation speed of 180rpm, shearing at the rotation speed of 2700rpm, and mixing for 5min;
tabletting: using a shallow concave punching die to perform tabletting, and placing the tablets into a rotary tablet machine to perform tabletting, wherein the hardness is controlled to be 80-150N, and the thickness of the tablets is controlled to be 4.1-4.5 mm.
2. Composition of controlled release film slurry (%, w/w)
Dissolving cellulose acetate and polyethylene glycol (PEG 4000) with acetone, and continuously coating the tablet core by using high-efficiency coating equipment, wherein the coating flow is about 100g/min, and the temperature of a tablet bed is about 30 ℃, until the weight gain of the obtained controlled-release film coating layer is 9% of that of the tablet core.
After the controlled release film is coated, medicine release holes are punched on the upper surface and the lower surface of the tablet by using a laser drilling machine, and the hole diameter is 0.5mm;
3. film coating
Preparing alcohol with proper concentration, and fully stirring and swelling the gastric soluble opadry; continuously coating the tablet cores by using a high-efficiency coating pan; the solid content of the coating liquid is controlled at 10%, the coating flow is about 80g/min, and the temperature of a tablet bed is about 30 ℃ until the weight of the obtained coating layer is increased to 5% of that of the tablet core.
4. Aging conditions
The film coated tablets were spread on a screen and cured according to the following conditions:
| batch number | Example 1-1 | Examples 1 to 2 | Examples 1 to 3 | Examples 1 to 4 | Examples 1 to 5 |
| Curing temperature/. |
60 | 65 | 70 | 75 | 80 |
| Aging time/ |
120 | 120 | 120 | 120 | 120 |
| Cooling time/ |
120 | 120 | 120 | 120 | 120 |
Example 2 controlled Release Membrane coating weight gain
1. Tablet core composition (mg/P)
Mixing dry powder: pouring oxycodone hydrochloride, a half amount of PEO500 million and other auxiliary materials into a wet mixing granulator, and mixing for 3min at a stirring speed of 180rpm and a shearing speed of 2700 rpm; adding 500 million of the residual PEO, stirring at the rotation speed of 180rpm, shearing at the rotation speed of 2700rpm, and mixing for 5min;
tabletting: tabletting by using a shallow concave punch die and a rotary tablet machine, and controlling the hardness to be 10-20 kg/m 2 The thickness of the control sheet is 4.1-4.5 mm.
2. Composition of controlled release film coat (%, w/w)
Dissolving cellulose acetate and polyethylene glycol (PEG 4000) with acetone, continuously coating tablet core with high-efficiency coating equipment at coating flow rate of 100g/min and tablet bed temperature of 30 deg.C,
the weight gain of the coating is controlled in the following range.
| Batch number | Example 2-1 | Examples 2 to 2 | Examples 2 to 3 |
| Coating weight gain/% | 10 | 8 | 5 |
After the controlled release film is coated, medicine release holes with the aperture of 0.5mm are punched on the upper surface and the lower surface of the tablet by using a laser drilling machine;
3. film coating
Preparing alcohol with proper concentration, and fully stirring and swelling the gastric-soluble Opadry; continuously coating the tablet cores by using a high-efficiency coating pan; the solid content of the coating liquid is controlled at 10%, the coating flow is about 80g/min, and the temperature of a tablet bed is about 30 ℃ until the weight of the obtained coating layer is increased to 5% of that of the tablet core.
4. Maturation conditions
Spreading the film coated tablet on a screen mesh, aging in an oven at 70 deg.C for 120min (counting time after oven temperature reaches 70 deg.C), taking out the sample, and cooling at room temperature for 120min.
EXAMPLE 3 tablet core composition
1. Tablet core composition (mg/P)
| Component (%)/batch number | Example 3-1 | Examples 3 to 2 | Examples 3 to 3 | Examples 3 to 4 | Examples 3 to 5 |
| |
10 | 10 | 10 | 10 | 10 |
| PEO500 million | 130 | 115 | 85 | 50 | 20 |
| PEO10 ten thousand | 0 | 15 | 45 | 80 | 110 |
| Hydroxypropyl cellulose | 9 | 9 | 9 | 9 | 9 |
| Magnesium stearate | 1 | 1 | 1 | 1 | 1 |
| Total amount of | 150 | 150 | 150 | 150 | 150 |
Mixing dry powder: pouring oxycodone hydrochloride, half PEO500 ten thousand, half PEO10 ten thousand and other auxiliary materials into a wet mixing granulator, stirring at a rotating speed of 180rpm, shearing at a rotating speed of 2700rpm, and mixing for 3min; adding 500 million of the residual PEO, stirring at the rotation speed of 180rpm, shearing at the rotation speed of 2700rpm, and mixing for 5min;
tabletting: and (3) carrying out tabletting by using a shallow concave punch die, and putting the tablet into a rotary tabletting machine for tabletting, wherein the hardness is controlled to be 80-150N, and the thickness of the tablet is controlled to be 4.1-4.5 mm.
2. Composition of controlled release film coating slurry (%, w/w)
Dissolving cellulose acetate and polyethylene glycol (PEG 4000) with acetone, and continuously coating the tablet core by using high-efficiency coating equipment, wherein the coating flow is about 100g/min, and the temperature of a tablet bed is about 30 ℃, until the weight gain of the obtained controlled-release film coating layer is 8% of that of the tablet core. After the controlled release film is coated, the upper and lower surfaces of the tablet are punched with drug release holes with the aperture of 0.5mm by using a laser drilling machine.
3. Film coating
Preparing alcohol with proper concentration, and fully stirring and swelling the gastric soluble opadry; continuously coating the tablet cores by using a high-efficiency coating pan; the solid content of the coating liquid is controlled at 10%, the coating flow is about 80g/min, the temperature of a tablet bed is about 30 ℃, and the weight increment of the coating is controlled within 5%.
4. Aging conditions
Spreading the film coated tablet on a screen mesh, placing in a 70 deg.C oven for aging for 120min (counting time after oven temperature reaches 70 deg.C), and taking out the sample and cooling at room temperature for 120min after aging.
Example 4
Tablet core composition (mg/P)
2. The production process is the same as that of example 3, wherein the upper and lower surfaces of the tablet are provided with drug release holes, and the hole diameter is 0.4mm;
3. the maturation conditions were the same as in example 3.
Example 5
Tablet core composition (mg/P)
2. The production process is the same as that of example 3, wherein the upper and lower surfaces of the tablet are provided with drug release holes, and the hole diameter is 0.6mm;
3. the maturation conditions were the same as in example 3.
Example 6
Tablet core composition (mg/P)
2. The production process is the same as that of example 3, wherein the upper and lower surfaces of the tablet are provided with drug release holes, and the hole diameter is 0.7mm;
3. the maturation conditions were the same as in example 3.
4. HPC used in this example was made by Ashland corporation and was model HF.
Release Rate and Release according to the published formulation (see publication No. US8894988, example 13.1)
Corresponding samples (comparative example 1) and
(production lot DB421, 10mg specification) preparation, according to the TEST1 release conditions of the United states pharmacopoeia oxycodone hydrochloride sustained release tablet item, the release curve TEST and the release uniformity investigation are carried out.
Comparative example 1
Tablet core composition (mg/P)
Mixing dry powder: the material was poured into a patterson Kelly "V" mixer in the following order: half of the PEO 400 ten thousand, oxycodone hydrochloride and the rest PEO 400 ten thousand are mixed for 5min; adding magnesium stearate, and mixing for 1min.
Tabletting: tabletting by using a shallow concave punch die, and tabletting by using a rotary tabletting machine.
Curing: placing the tablet core in a 24-inch compu-lab coating pan, setting the rotation speed of the pan to be 7rpm, setting the target temperature of a probe to be 75 ℃, and curing for 90min when the temperature reaches 70 ℃ as a curing starting point; at the end of the maturation, magnesium stearate is added to the moving core as an anti-tack agent. After coating, ventilating and cooling at 21-25 ℃.
The weight of the coating is increased by 4 to 6 percent.
Comparative example 2
Products on the market
Product information: specification 10mg/tablet, batch number: DB421.
Measurement of Release degree
The operation is as follows: taking the product by HPLC method, according to a release degree determination USP pharmacopoeia oxycodone hydrochloride sustained release tablet TEST1 device, taking artificial gastric juice (without enzyme) as release medium 900ml, basket method, rotating speed of 100 r/min, operating according to the method, respectively taking solution 5ml after 1, 2, 4, 6, 8 and 12 hours, filtering, and timely supplementing release medium with the same temperature and volume. Detecting the release amount of the test solution by an HPLC method at a wavelength of 254 nm; another oxycodone hydrochloride reference substance is precisely weighed, and is dissolved and quantitatively diluted by adding phosphate buffer solution to prepare a solution containing about 0.1mg in each 1ml as a reference substance solution, and the solution is measured by the same method.
The examples were evaluated for release according to the above release detection method. The measured release of each example is shown in table 1; the release of each example is plotted, and the results of examples 1-6 are shown in FIGS. 1-4; comparative example 1 to comparative example 2 see fig. 5.
Table 1: examples Release Rate data (%)
Analysis and evaluation of experimental results:
the results of the release degrees of the examples 1-1 to 1-5 have no significant difference, and the results show that the curing temperature has no significant influence on the release degree of the preparation.
The release rate results of the examples 2-1 to 2-3 show that the release rate is reduced along with the increase of the weight of the controlled release film coating, and no significant difference exists in the range of 5 to 10 percent of the weight.
The results of the release degrees of the examples 3-1 to 3-5 show that when the proportion of PEO500 in the tablet core is more than 50%, the release rates are not obviously different; at a PEO500 ten thousand percent ratio of 20%, the release rate became significantly faster.
The release results of example 4, example 5 and example 6 show that the change of the type of the adhesive in the tablet core has no significant influence on the release rate.
Compared with the comparative examples 1 and 2, the in vitro release trend of the sample prepared by the embodiment of the invention is more gentle, the stable release of the medicine is facilitated, and the product can play a longer-time analgesic effect under the same dosage, so that the medicine taking times and dosage of the medicine can be reduced, the medicine circulation on the market can be reduced, and the difficulty in obtaining the product through illegal ways is higher, so that the abuse is reduced. The medicine taking frequency is reduced, and the medicine taking compliance and the safety of a patient can be improved.
Tablet compression resistance test
The samples prepared in examples and comparative examples were pressed with a DTKJ-63 pneumatic press (automated technologies ltd., wenzhou dingteng) at a pressure of 400N and 7 hammering times, and the state of the samples after hammering, including the integrity and the size of the edge crack, was observed. The compression resistance results are shown in FIGS. 6 to 9.
The self-ground articles (samples prepared according to inventive examples 1-3, 3-3) had better integrity after peening, less edge cracking, less cracking, and less damage to the self-ground article from peening than comparative example 1 and comparative example 2.
The self-grinding product is more difficult to crush and destroy, and the active substances in the self-grinding product are more difficult to extract, so that the abuse of drugs can be reduced to a greater extent. The effect of the invention on reducing abuse by the oral route is more evident than the comparative examples.
Pharmacokinetic Studies
1.1 instruments
Analyst 1.5.1 workstation (AB SCIEX, USA); DGU-20A3 online degasser, LC-20AD liquid chromatography infusion pump, SIL-20AC temperature-controllable autosampler, CTO-20AC column oven (Shimadzu corporation, japan); AG-285 electronic analytical balance (mettler-toledo instruments ltd); genius 3 model autovortexer, high speed refrigerated centrifuge (semer-feishell scientific instruments ltd).
1.2 drugs and reagents
Test formulations: oxycodone hydrochloride sustained-release tablets, specification: 10mg/tablet (prepared as in examples 1-3); reference formulation:
(developed and manufactured by Purdue, specification: 10 mg/tablet); oxycodone hydrochloride control (china institute for drug and biological products). Methanol (SIGMA corporation)Chromatographically pure); acetonitrile (SIGMA, chromatographically pure); ammonium acetate (alatin, chromatographically pure); water (double distilled water, self-made)
1.3 dosing regimens and blood sample Collection
8 healthy adult Beagle dogs with an average body weight of 15.5kg (13.2-17.6 kg). Each preparation is orally administered for 1 tablet, venous blood 3ml is taken after 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h and 12h after administration, and centrifuged at 5000rpm for 20min.
1.4 chromatographic and Mass Spectrometry conditions
Chromatographic conditions are as follows: octyl silane bonded silica gel is used as a filling agent; 1.1g/L sodium 1-heptanesulfonate buffer (adjusted to pH 2.0 with phosphoric acid): acetonitrile: methanol = 700; the detection wavelength is 2 30nm; the column temperature is 40 ℃; sample injection amount: 40 μ L.
The results for the tested formulations are shown in table 2; the results for the reference formulation are shown in table 3, and figures 10-11. The relative bioavailability is 123.5% + -14.2%. The pharmacokinetic parameter ln (AUC 0-t) 90% confidence interval of the tested preparation is in the range of 80% -125% of the reference preparation, ln (Cmax) is in the range of 75% -133% of the reference preparation, tmax has no significant difference through nonparametric inspection, and the tested preparation is bioequivalent to the reference preparation.
TABLE 2 blood concentration-time curves of the test formulations after single drench administration of the test formulations to Beagle dogs
TABLE 3 blood concentration-time curves of the reference formulation after single drench administration of the test formulation in Beagle dogs
Claims (21)
1. The oxycodone hydrochloride sustained-release tablet is characterized by comprising a tablet core, a controlled-release coating and a film coating, wherein the tablet core comprises the following components in percentage by weight of the tablet core:
wherein the weight gain of the controlled release film coat is 1-20% of the weight of the tablet core; the weight increment of the film coat is 1-15% of the weight of the tablet core.
2. Sustained release tablet according to claim 1, characterized in that the release modifier is present in an amount of 50 to 95%, preferably 80 to 95% by weight of the core.
3. The sustained-release tablet according to claim 2, wherein the release modifier is selected from polyoxyethylene, which is a polyoxyethylene having a molecular weight of 10 ten thousand or more, preferably a polyoxyethylene having a molecular weight of 10 ten thousand to 700 ten thousand; or a combination of polyoxyethylene of different molecular weights in the range of 10 to 700 million.
4. The sustained-release tablet according to claim 3, wherein the release modifier is selected from polyoxyethylene of 100 to 700 ten thousand molecular weight; preferably 200 to 700 ten thousand molecular weight polyoxyethylene, more preferably 400 to 600 ten thousand molecular weight polyoxyethylene, and preferably 500 ten thousand molecular weight polyoxyethylene.
5. The sustained-release tablet according to claim 3, wherein the release modifier is selected from the group consisting of a combination of 10 ten thousand molecular weight polyoxyethylene and 500 ten thousand molecular weight polyoxyethylene; preferably, the weight portion ratio of 10 ten thousand to 500 ten thousand of the polyoxyethylene is 15; more preferably 15.
6. The sustained-release tablet according to claim 5, wherein the release modifier is selected from the group consisting of polyoxyethylene of 10 ten thousand molecular weight and polyoxyethylene of 500 ten thousand molecular weight, wherein the ratio of the polyoxyethylene of 10 ten thousand molecular weight to the polyoxyethylene of 500 ten thousand molecular weight is 15 parts by weight, 45 parts by weight, 85 parts by weight, or 80 parts by weight.
7. Sustained-release tablet according to claim 1, characterized in that the binder is used in an amount of 2-8%, preferably 5-8% by weight of the core.
8. The sustained-release tablet of claim 7, wherein the binder comprises starch, dextrin, gelatin, polyethylene glycol, methylcellulose, hydroxypropylcellulose, povidone, or hydroxypropylmethylcellulose, or a combination of two or more thereof; hydroxypropylcellulose is preferred.
9. Sustained release tablet according to claim 1, characterized in that the lubricant is used in an amount of 0.1 to 4%, preferably 0.2 to 2% by weight of the tablet core.
10. The sustained-release tablet according to claim 9, wherein the lubricant is magnesium stearate, aerosil, talc, or sodium lauryl sulfate, or a combination of two or more thereof; magnesium stearate is preferred.
11. The sustained release tablet of claim 1, wherein the weight gain of the controlled release film coat is 3.0 to 12.0 percent of the weight of the tablet core, preferably 6.0 to 10.0 percent.
12. The sustained-release tablet of claim 11, wherein the controlled-release film coat comprises a film-forming material, a pore-forming agent, and a coating solvent.
13. The sustained-release tablet of claim 12, wherein the film-forming material is cellulose acetate, ethyl cellulose, an ethylene-vinyl acetate copolymer, a methacrylate copolymer, or a combination of two or more thereof; preferably cellulose acetate;
the dosage of the film forming material is 1 to 30 percent, preferably 1.0 to 10.0 percent, and more preferably 1.0 to 6.0 percent based on the weight of the controlled release film coat.
14. The sustained-release tablet according to claim 12, wherein the pore-forming agent is polyethylene glycol (PEG 4000), povidone, hypromellose, polysorbate, sorbitan fatty acid ester, polyvinyl alcohol, lactose, or a combination of two or more thereof; preferably polyethylene glycol (PEG 4000);
the dosage of the pore-forming agent is 0.1-20% by weight of the controlled release coating, preferably 0.5-15.0%, more preferably 0.5-5.0%, and even more preferably 1.0-4.0%.
15. The sustained-release tablet according to claim 12, wherein the solvent used for the controlled-release film coating is selected from methanol, ethanol, acetone, dichloromethane or water, or a combination of two or more thereof; the dosage is 50 to 95 percent, preferably 80.0 to 95.0 percent based on the weight of the controlled release film coating.
16. The sustained-release tablet of claim 12, wherein the two or more combinations are selected from the group consisting of a combination of acetone and ethanol, a combination of acetone and methanol, a mixture of acetone and water, and a mixture of dichloromethane and ethanol.
17. The sustained-release tablet of claim 12, wherein the controlled-release film coating solvent is selected from acetone.
18. Sustained-release tablet according to claim 1, characterized in that the weight gain of the film coat is 1.0-8.0%, preferably 3-6%, more preferably 3.0-5.0% of the weight of the tablet core.
19. A process for the preparation of the extended release tablet as claimed in any one of claims 1 to 18, wherein the process comprises the steps of:
1) Mixing the dry powder;
2) Tabletting;
3) Coating a controlled release film coat, and performing laser drilling;
4) Coating with a film;
5) Curing;
6) And (6) cooling.
20. The method of manufacturing according to claim 19, further comprising:
1) Mixing dry powder: mixing oxycodone hydrochloride and other auxiliary materials uniformly;
2) Tabletting: tabletting by using a rotary tablet machine, controlling the hardness to be 80-150N, preferably 90-140N, and controlling the thickness of the tablet to be 4-4.8 mm, preferably 4.1-4.5 mm;
3) Coating with a controlled release film: dissolving a film forming material and a pore-forming agent by using a controlled-release film coating solvent, and carrying out isolated coating on the tablet core by using high-efficiency coating equipment, wherein the coating temperature is controlled to be 20-50 ℃, and the weight increment of the controlled-release film coating is 1.0-20.0% of the weight of the tablet core, preferably 3.0-12.0%, and more preferably 6.0-10.0%; after coating the controlled release film, respectively drilling a drug release hole on the upper surface and the lower surface of the tablet by using a laser drilling machine, wherein the hole diameter is controlled to be 0.2 mm-0.8 mm, preferably 0.4 mm-0.8 mm, and preferably 0.6 mm-0.8 mm;
4) Film coating: dissolving a coating material by using a film coating solvent, and carrying out isolated coating on the tablet core by using high-efficiency or fluidized bed coating equipment, wherein the coating temperature is controlled to be 20-50 ℃, and the weight increment of the film coating is 1-15% of the weight of the tablet core, preferably 1.0-8.0%, and more preferably 3-6%.
5) Curing: curing the film-coated tablets by using a drying oven or a coating pan, wherein the curing temperature is controlled to be 60-90 ℃, and preferably 70-80 ℃; the curing time is 1 to 8 hours, preferably 2 to 5 hours;
6) And (3) cooling: cooling the cured film-coated tablet at normal temperature.
21. The method of claim 20, wherein the step 1) further comprises: pouring oxycodone hydrochloride, half amount of polyoxyethylene and other auxiliary materials into a wet mixing granulator, and stirring at the rotating speed of 30-200 rpm, preferably 50-180 rpm, more preferably 110-180 rpm; the shearing speed is 300 to 4000rpm, preferably 1000 to 3000rpm, more preferably 2000 to 2800rpm; mixing for 1-10 min, preferably 2-6 min, more preferably 2-5 min; then adding the rest polyoxyethylene, and stirring at the rotating speed of 30-200 rpm, preferably 50-180 rpm, more preferably 110-180 rpm; the shearing speed is 300-4000 rpm, preferably 1000-3000 rpm, more preferably 2000-2800 rpm; mixing for 1min to 10min, preferably 2min to 6min, more preferably 2 to 5min.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5266331A (en) * | 1991-11-27 | 1993-11-30 | Euroceltique, S.A. | Controlled release oxycodone compositions |
| WO2006002884A1 (en) * | 2004-07-01 | 2006-01-12 | Grünenthal GmbH | Oral dosage form safeguarded against abuse |
| US20090175937A1 (en) * | 2007-12-17 | 2009-07-09 | Labopharm, Inc. | Misuse Preventative, Controlled Release Formulation |
| CN105878204A (en) * | 2014-12-16 | 2016-08-24 | 合肥立方制药股份有限公司 | Metformin hydrochloride osmotic pump controlled release tablet and preparation method thereof |
-
2021
- 2021-08-13 CN CN202110928594.2A patent/CN115702888B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5266331A (en) * | 1991-11-27 | 1993-11-30 | Euroceltique, S.A. | Controlled release oxycodone compositions |
| WO2006002884A1 (en) * | 2004-07-01 | 2006-01-12 | Grünenthal GmbH | Oral dosage form safeguarded against abuse |
| US20090175937A1 (en) * | 2007-12-17 | 2009-07-09 | Labopharm, Inc. | Misuse Preventative, Controlled Release Formulation |
| CN105878204A (en) * | 2014-12-16 | 2016-08-24 | 合肥立方制药股份有限公司 | Metformin hydrochloride osmotic pump controlled release tablet and preparation method thereof |
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| CN115702888B (en) | 2024-05-28 |
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